NM_002474.3:c.*631C>T

Variant names:

• chr16-15703360-G-A
• rs112926446
• NM_002474.3:c.*631C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_002474.3(MYH11):​c.*631C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0068 in 236,244 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0062 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0079 (7 hom.)
• Consequence: MYH11 NM_002474.3 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.06
• 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 16-15703360-G-A is Benign according to our data. Variant chr16-15703360-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 887908.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0062 (944/152264) while in subpopulation NFE AF = 0.0102 (693/68014). AF 95% confidence interval is 0.00956. There are 3 homozygotes in GnomAd4. There are 433 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 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.*631C>T		3_prime_UTR	Exon 41 of 41	NP_002465.1	P35749-1
	MYH11	NM_001040113.2	MANE Plus Clinical	c.*772C>T		3_prime_UTR	Exon 43 of 43	NP_001035202.1	P35749-3
	NDE1	NM_017668.3	MANE Select	c.947+6500G>A		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.*631C>T		3_prime_UTR	Exon 41 of 41	ENSP00000300036.5	P35749-1
	MYH11	ENST00000452625.7	TSL:1 MANE Plus Clinical	c.*772C>T		3_prime_UTR	Exon 43 of 43	ENSP00000407821.2	P35749-3
	MYH11	ENST00000396324.7	TSL:1	c.*631C>T		3_prime_UTR	Exon 42 of 42	ENSP00000379616.3	P35749-2

Frequencies

GnomAD3 genomes AF: 0.00621 AC: 945 AN: 152146 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00200

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.00557

Gnomad ASJ AF: 0.00346

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00509

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0102

Gnomad OTH AF: 0.00573

GnomAD4 exome AF: 0.00789 AC: 663 AN: 83980 Hom.: 7 Cov.: 0 AF XY: 0.00820 AC XY: 323 AN XY: 39372

African (AFR) AF: 0.000556 AC: 2 AN: 3596

American (AMR) AF: 0.00525 AC: 22 AN: 4192

Ashkenazi Jewish (ASJ) AF: 0.00288 AC: 14 AN: 4856

East Asian (EAS) AF: 0.00 AC: 0 AN: 11298

South Asian (SAS) AF: 0.00 AC: 0 AN: 1646

European-Finnish (FIN) AF: 0.0172 AC: 2 AN: 116

Middle Eastern (MID) AF: 0.00211 AC: 1 AN: 474

European-Non Finnish (NFE) AF: 0.0112 AC: 575 AN: 51166

Other (OTH) AF: 0.00708 AC: 47 AN: 6636

GnomAD4 genome AF: 0.00620 AC: 944 AN: 152264 Hom.: 3 Cov.: 32 AF XY: 0.00582 AC XY: 433 AN XY: 74432

African (AFR) AF: 0.00200 AC: 83 AN: 41564

American (AMR) AF: 0.00556 AC: 85 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00346 AC: 12 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4820

European-Finnish (FIN) AF: 0.00509 AC: 54 AN: 10610

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

European-Non Finnish (NFE) AF: 0.0102 AC: 693 AN: 68014

Other (OTH) AF: 0.00567 AC: 12 AN: 2116

Alfa AF: 0.00706 Hom.: 0

Bravo AF: 0.00625

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Aortic aneurysm, familial thoracic 4 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	7.5
DANN	Benign	0.76
PhyloP100		1.1
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs112926446; hg19: chr16-15797217;