rs184810732

chr12-57029440-T-C

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP6 BS2

The NM_005379.4(MYO1A):c.2872A>G(p.Ser958Gly) variant causes a missense change. The variant allele was found at a frequency of 0.0000886 in 1,613,920 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000081 (1 hom.)
• Consequence: MYO1A NM_005379.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 5.80

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 -5 ACMG points.

• BP6: Variant 12-57029440-T-C is Benign according to our data. Variant chr12-57029440-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 164579.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=1}.
• BS2: High AC in GnomAd at 19 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYO1A	NM_005379.4	c.2872A>G	p.Ser958Gly	missense_variant	26/28	ENST00000300119.8
MYO1A	NM_001256041.2	c.2872A>G	p.Ser958Gly	missense_variant	27/29
MYO1A	XM_047428876.1	c.2872A>G	p.Ser958Gly	missense_variant	27/29

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYO1A	ENST00000300119.8	c.2872A>G	p.Ser958Gly	missense_variant	26/28	1	NM_005379.4	P1
MYO1A	ENST00000442789.6	c.2872A>G	p.Ser958Gly	missense_variant	27/29	1		P1
MYO1A	ENST00000477864.1	n.435A>G		non_coding_transcript_exon_variant	4/4	2
MYO1A	ENST00000554234.5	c.*317A>G		3_prime_UTR_variant, NMD_transcript_variant	22/24	5

Frequencies

GnomAD3 genomes AF: 0.000125 AC: 19 AN: 151936 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: 0.00309

Gnomad SAS AF: 0.000416

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000263 AC: 66 AN: 251288 Hom.: 0 AF XY: 0.000302 AC XY: 41 AN XY: 135796

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00277

Gnomad SAS exome AF: 0.000359

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.0000814 AC: 119 AN: 1461866 Hom.: 1 Cov.: 33 AF XY: 0.000107 AC XY: 78 AN XY: 727232

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00123

Gnomad4 SAS exome AF: 0.000464

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000450

Gnomad4 OTH exome AF: 0.000397

GnomAD4 genome AF: 0.000158 AC: 24 AN: 152054 Hom.: 0 Cov.: 32 AF XY: 0.000161 AC XY: 12 AN XY: 74334

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00310

Gnomad4 SAS AF: 0.000416

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.0000663 Hom.: 0

Bravo AF: 0.0000982

ExAC AF: 0.000222 AC: 27

Asia WGS AF: 0.0140 AC: 48 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Apr 10, 2013

Variant classified as Uncertain Significance - Favor Benign. The Ser958Gly varia nt in MYO1A has not been reported in individuals affected with hearing loss, but has been identified in 3/340 (0.9%) of Chinese chromosomes by the 1000 Genomes Project (dbSNP rs184810732). Although this variant has been seen in the general population, the sample size is too small to rule out a pathogenic role. Computa tional analyses (biochemical amino acid properties, conservation, AlignGVGD, Pol yPhen2, and SIFT) suggest that the Ser958Gly variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, the clinical significance of this variant cannot be determined with cer tainty; however, based upon its presence in the 1000 Genome database and the com putational assessment, we lean towards a more likely benign role. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Dec 06, 2016

- -

MYO1A-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 28, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.35
Cadd	Pathogenic	31
Dann	Uncertain	0.99
DEOGEN2	Benign	0.046	T;T
Eigen	Benign	-0.017
Eigen_PC	Benign	0.12
FATHMM_MKL	Uncertain	0.94	D
M_CAP	Benign	0.046	D
MetaRNN	Benign	0.012	T;T
MetaSVM	Uncertain	-0.23	T
MutationAssessor	Uncertain	2.3	M;M
MutationTaster	Benign	0.85	N;N;N
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-1.3	N;N
REVEL	Uncertain	0.31
Sift	Benign	0.11	T;T
Sift4G	Benign	0.28	T;T
Polyphen		0.024	B;B
Vest4		0.21
MVP		0.81
MPC		0.097
ClinPred		0.070	T
GERP RS		4.5
Varity_R		0.12
gMVP		0.082

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.76		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.76		Position offset: 0
DS_DL_spliceai		0.32		Position offset: -5

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

Publications

LitVar

Other links and lift over

dbSNP: rs184810732; hg19: chr12-57423224;