chr16-15703954-G-T

Variant names:

• chr16-15703954-G-T
• rs182768107
• NM_002474.3:c.*37C>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_002474.3(MYH11):​c.*37C>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000541 in 1,613,108 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00056 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00054 (14 hom.)
• Consequence: MYH11 NM_002474.3 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.141
• Publications: 1 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: Labcorp Genetics (formerly Invitae), PanelApp Australia, Laboratory for Molecular Medicine, Ambry Genetics, G2P
• microcephaly with lissencephaly and/or hydranencephaly

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• hydranencephaly

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

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

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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 16-15703954-G-T is Benign according to our data. Variant chr16-15703954-G-T is described in ClinVar as Likely_benign. ClinVar VariationId is 318086.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000559 (85/152006) while in subpopulation EAS AF = 0.0146 (75/5146). AF 95% confidence interval is 0.0119. There are 1 homozygotes in GnomAd4. There are 52 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 14 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002474.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYH11	NM_002474.3	MANE Select	c.*37C>A		3_prime_UTR	Exon 41 of 41	NP_002465.1	P35749-1
	MYH11	NM_001040113.2	MANE Plus Clinical	c.*178C>A		3_prime_UTR	Exon 43 of 43	NP_001035202.1	P35749-3
	NDE1	NM_017668.3	MANE Select	c.947+7094G>T		intron	N/A	NP_060138.1	Q9NXR1-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYH11	ENST00000300036.6	TSL:1 MANE Select	c.*37C>A		3_prime_UTR	Exon 41 of 41	ENSP00000300036.5	P35749-1
	MYH11	ENST00000452625.7	TSL:1 MANE Plus Clinical	c.*178C>A		3_prime_UTR	Exon 43 of 43	ENSP00000407821.2	P35749-3
	MYH11	ENST00000396324.7	TSL:1	c.*37C>A		3_prime_UTR	Exon 42 of 42	ENSP00000379616.3	P35749-2

Frequencies

GnomAD3 genomes AF: 0.000560 AC: 85 AN: 151888 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000657

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0145

Gnomad SAS AF: 0.00187

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00160 AC: 402 AN: 251462 AF XY: 0.00144

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0210

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000977

GnomAD4 exome AF: 0.000539 AC: 787 AN: 1461102 Hom.: 14 Cov.: 31 AF XY: 0.000515 AC XY: 374 AN XY: 726854

African (AFR) AF: 0.00 AC: 0 AN: 33464

American (AMR) AF: 0.00 AC: 0 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26114

East Asian (EAS) AF: 0.0179 AC: 709 AN: 39672

South Asian (SAS) AF: 0.000476 AC: 41 AN: 86144

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53306

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5762

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1111568

Other (OTH) AF: 0.000530 AC: 32 AN: 60366

GnomAD4 genome AF: 0.000559 AC: 85 AN: 152006 Hom.: 1 Cov.: 32 AF XY: 0.000700 AC XY: 52 AN XY: 74282

African (AFR) AF: 0.00 AC: 0 AN: 41456

American (AMR) AF: 0.0000656 AC: 1 AN: 15250

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.0146 AC: 75 AN: 5146

South Asian (SAS) AF: 0.00187 AC: 9 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10580

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67974

Other (OTH) AF: 0.00 AC: 0 AN: 2110

Alfa AF: 0.000101 Hom.: 0

Bravo AF: 0.000691

Asia WGS AF: 0.00577 AC: 20 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Aortic aneurysm, familial thoracic 4 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.41
DANN	Benign	0.56
PhyloP100		-0.14
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs182768107; hg19: chr16-15797811;