12-57043919-C-T

Variant names:

• chr12-57043919-C-T
• rs141826192
• NM_005379.4:c.829G>A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_005379.4(MYO1A):​c.829G>A​(p.Val277Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000923 in 1,614,066 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00018 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000083 (1 hom.)
• Consequence: MYO1A NM_005379.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.14

Genes affected

MYO1A (HGNC:7595): (myosin IA) This gene encodes a member of the myosin superfamily. The protein represents an unconventional myosin; it should not be confused with the conventional skeletal muscle myosin-1 (MYH1). Unconventional myosins contain the basic domains characteristic of conventional myosins and are further distinguished from class members by their tail domains. They function as actin-based molecular motors. Mutations in this gene have been associated with autosomal dominant deafness. Alternatively spliced variants have been found for this gene. [provided by RefSeq, Dec 2011]

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• BS2: High AC in GnomAd4 at 27 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYO1A	NM_005379.4	c.829G>A	p.Val277Met	missense_variant	Exon 10 of 28	ENST00000300119.8	NP_005370.1
MYO1A	NM_001256041.2	c.829G>A	p.Val277Met	missense_variant	Exon 11 of 29		NP_001242970.1
MYO1A	XM_047428876.1	c.829G>A	p.Val277Met	missense_variant	Exon 11 of 29		XP_047284832.1
MYO1A	XM_011538373.3	c.829G>A	p.Val277Met	missense_variant	Exon 10 of 25		XP_011536675.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYO1A	ENST00000300119.8	c.829G>A	p.Val277Met	missense_variant	Exon 10 of 28	1	NM_005379.4	ENSP00000300119.3
MYO1A	ENST00000442789.6	c.829G>A	p.Val277Met	missense_variant	Exon 11 of 29	1		ENSP00000393392.2
MYO1A	ENST00000492945.5	c.-20-561G>A		intron_variant	Intron 2 of 4	4		ENSP00000452229.1
MYO1A	ENST00000554234.5	n.343G>A		non_coding_transcript_exon_variant	Exon 6 of 24	5		ENSP00000451033.1

Frequencies

GnomAD3 genomes AF: 0.000177 AC: 27 AN: 152176 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000770

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000250

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.0000836 AC: 21 AN: 251140 Hom.: 0 AF XY: 0.000111 AC XY: 15 AN XY: 135714

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000260

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000272

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000617

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000835 AC: 122 AN: 1461890 Hom.: 1 Cov.: 32 AF XY: 0.0000866 AC XY: 63 AN XY: 727246

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000126

Gnomad4 SAS exome AF: 0.0000696

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.0000827

Gnomad4 OTH exome AF: 0.000132

GnomAD4 genome AF: 0.000177 AC: 27 AN: 152176 Hom.: 0 Cov.: 32 AF XY: 0.000188 AC XY: 14 AN XY: 74364

Gnomad4 AFR AF: 0.0000483

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000770

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000250

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.000165 Hom.: 0

Bravo AF: 0.000212

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.0000494 AC: 6

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 30, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Val277Met variant in MYO1A has not been previously reported in individuals with hearing loss, but has been identified in 0.03% (3/8600) of European Americ an chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.e du/EVS/; dbSNP rs141826192). Computational prediction tools and conservation ana lysis do not provide strong support for or against an impact to the protein. The clinical significance of the Val277Met variant is uncertain. However, recent ev idence has disqualified an association between variants in this gene and hearing loss and therefore the p.Val277Met variant is unlikely to be causative for hear ing loss (Eisenberger 2014). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.020	T
BayesDel_noAF	Uncertain	0.030
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.47	T;T
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Uncertain	0.96	.;D
M_CAP	Uncertain	0.091	D
MetaRNN	Uncertain	0.48	T;T
MetaSVM	Uncertain	0.43	D
MutationAssessor	Benign	1.6	L;L
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-2.0	N;N
REVEL	Uncertain	0.58
Sift	Uncertain	0.0030	D;D
Sift4G	Uncertain	0.0050	D;D
Polyphen		1.0	D;D
Vest4		0.31
MVP		0.87
MPC		0.35
ClinPred		0.24	T
GERP RS		5.3
Varity_R		0.43
gMVP		0.57

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

Publications

LitVar

Other links and lift over

dbSNP: rs141826192; hg19: chr12-57437703; COSMIC: COSV55658049; COSMIC: COSV55658049;