16-15721638-C-T

Variant names:

• chr16-15721638-C-T
• rs760252350
• NM_002474.3:c.4366-4G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BP6_Very_Strong

The NM_002474.3(MYH11):​c.4366-4G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000013 in 1,614,172 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: MYH11 NM_002474.3 splice_region, intron
• Scores: Splicing: ADA: 0.00006354
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0950
• Publications: 0 publications found

Genes affected

MYH11 (HGNC:7569): (myosin heavy chain 11) The protein encoded by this gene is a smooth muscle myosin belonging to the myosin heavy chain family. The gene product is a subunit of a hexameric protein that consists of two heavy chain subunits and two pairs of non-identical light chain subunits. It functions as a major contractile protein, converting chemical energy into mechanical energy through the hydrolysis of ATP. A chromosomal rearrangement involving this gene is associated with acute myeloid leukemia of the M4Eo subtype. Mutations in this gene are associated with visceral myopathy, megacystis-microcolon-intestinal hypoperistalsis syndrome 2, and familial thoracic aortic aneurysm 4. [provided by RefSeq, May 2022]

NDE1 (HGNC:17619): (nudE neurodevelopment protein 1) This gene encodes a member of the nuclear distribution E (NudE) family of proteins. The encoded protein is localized at the centrosome and interacts with other centrosome components as part of a multiprotein complex that regulates dynein function. This protein plays an essential role in microtubule organization, mitosis and neuronal migration. Mutations in this gene cause lissencephaly 4, a disorder characterized by lissencephaly, severe brain atrophy, microcephaly, and severe cognitive disability. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Mar 2012]

NDE1 Gene-Disease associations (from GenCC):

• lissencephaly 4

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: PanelApp Australia, Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine
• hydranencephaly

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• microlissencephaly

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• NDE1-related microhydranencephaly

  Inheritance: Unknown, AR Classification: SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 16-15721638-C-T is Benign according to our data. Variant chr16-15721638-C-T is described in CliVar as Likely_benign. Clinvar id is 413428.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-15721638-C-T is described in CliVar as Likely_benign. Clinvar id is 413428.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-15721638-C-T is described in CliVar as Likely_benign. Clinvar id is 413428.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-15721638-C-T is described in CliVar as Likely_benign. Clinvar id is 413428.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-15721638-C-T is described in CliVar as Likely_benign. Clinvar id is 413428.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-15721638-C-T is described in CliVar as Likely_benign. Clinvar id is 413428.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-15721638-C-T is described in CliVar as Likely_benign. Clinvar id is 413428.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-15721638-C-T is described in CliVar as Likely_benign. Clinvar id is 413428.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-15721638-C-T is described in CliVar as Likely_benign. Clinvar id is 413428.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-15721638-C-T is described in CliVar as Likely_benign. Clinvar id is 413428.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-15721638-C-T is described in CliVar as Likely_benign. Clinvar id is 413428.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-15721638-C-T is described in CliVar as Likely_benign. Clinvar id is 413428.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-15721638-C-T is described in CliVar as Likely_benign. Clinvar id is 413428.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-15721638-C-T is described in CliVar as Likely_benign. Clinvar id is 413428.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-15721638-C-T is described in CliVar as Likely_benign. Clinvar id is 413428.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-15721638-C-T is described in CliVar as Likely_benign. Clinvar id is 413428.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-15721638-C-T is described in CliVar as Likely_benign. Clinvar id is 413428.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-15721638-C-T is described in CliVar as Likely_benign. Clinvar id is 413428.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-15721638-C-T is described in CliVar as Likely_benign. Clinvar id is 413428.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-15721638-C-T is described in CliVar as Likely_benign. Clinvar id is 413428.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-15721638-C-T is described in CliVar as Likely_benign. Clinvar id is 413428.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-15721638-C-T is described in CliVar as Likely_benign. Clinvar id is 413428.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-15721638-C-T is described in CliVar as Likely_benign. Clinvar id is 413428.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-15721638-C-T is described in CliVar as Likely_benign. Clinvar id is 413428.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-15721638-C-T is described in CliVar as Likely_benign. Clinvar id is 413428.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-15721638-C-T is described in CliVar as Likely_benign. Clinvar id is 413428.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-15721638-C-T is described in CliVar as Likely_benign. Clinvar id is 413428.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-15721638-C-T is described in CliVar as Likely_benign. Clinvar id is 413428.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-15721638-C-T is described in CliVar as Likely_benign. Clinvar id is 413428.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-15721638-C-T is described in CliVar as Likely_benign. Clinvar id is 413428.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-15721638-C-T is described in CliVar as Likely_benign. Clinvar id is 413428.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-15721638-C-T is described in CliVar as Likely_benign. Clinvar id is 413428.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-15721638-C-T is described in CliVar as Likely_benign. Clinvar id is 413428.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-15721638-C-T is described in CliVar as Likely_benign. Clinvar id is 413428.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-15721638-C-T is described in CliVar as Likely_benign. Clinvar id is 413428.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-15721638-C-T is described in CliVar as Likely_benign. Clinvar id is 413428.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-15721638-C-T is described in CliVar as Likely_benign. Clinvar id is 413428.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-15721638-C-T is described in CliVar as Likely_benign. Clinvar id is 413428.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-15721638-C-T is described in CliVar as Likely_benign. Clinvar id is 413428.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-15721638-C-T is described in CliVar as Likely_benign. Clinvar id is 413428.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-15721638-C-T is described in CliVar as Likely_benign. Clinvar id is 413428.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-15721638-C-T is described in CliVar as Likely_benign. Clinvar id is 413428.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-15721638-C-T is described in CliVar as Likely_benign. Clinvar id is 413428.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-15721638-C-T is described in CliVar as Likely_benign. Clinvar id is 413428.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-15721638-C-T is described in CliVar as Likely_benign. Clinvar id is 413428.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYH11	NM_002474.3	c.4366-4G>A		splice_region_variant, intron_variant	Intron 31 of 40	ENST00000300036.6	NP_002465.1
MYH11	NM_001040113.2	c.4387-4G>A		splice_region_variant, intron_variant	Intron 32 of 42	ENST00000452625.7	NP_001035202.1
NDE1	NM_017668.3	c.948-2553C>T		intron_variant	Intron 8 of 8	ENST00000396354.6	NP_060138.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYH11	ENST00000300036.6	c.4366-4G>A		splice_region_variant, intron_variant	Intron 31 of 40	1	NM_002474.3	ENSP00000300036.5
MYH11	ENST00000452625.7	c.4387-4G>A		splice_region_variant, intron_variant	Intron 32 of 42	1	NM_001040113.2	ENSP00000407821.2
NDE1	ENST00000396354.6	c.948-2553C>T		intron_variant	Intron 8 of 8	1	NM_017668.3	ENSP00000379642.1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152206 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000239 AC: 6 AN: 251378 AF XY: 0.0000221

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000123 AC: 18 AN: 1461848 Hom.: 0 Cov.: 32 AF XY: 0.0000138 AC XY: 10 AN XY: 727236

African (AFR) AF: 0.0000299 AC: 1 AN: 33480

American (AMR) AF: 0.0000671 AC: 3 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53402

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.00000989 AC: 11 AN: 1111984

Other (OTH) AF: 0.0000331 AC: 2 AN: 60396

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152324 Hom.: 0 Cov.: 32 AF XY: 0.0000268 AC XY: 2 AN XY: 74490

African (AFR) AF: 0.00 AC: 0 AN: 41576

American (AMR) AF: 0.00 AC: 0 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68024

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.0000487 Hom.: 0

Bravo AF: 0.0000302

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial thoracic aortic aneurysm and aortic dissection Benign:1

Jul 20, 2020

Color Diagnostics, LLC DBA Color Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aortic aneurysm, familial thoracic 4 Benign:1

Aug 24, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	1.1
DANN	Benign	0.78
PhyloP100		-0.095
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000064
dbscSNV1_RF	Benign	0.0060
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs760252350; hg19: chr16-15815495;