rs55679042

chr12-57043335-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Moderate BP6_Very_Strong BS2

The NM_005379.4(MYO1A):c.916G>A(p.Val306Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00789 in 1,614,104 control chromosomes in the GnomAD database, including 46 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0055 (5 hom., cov: 32)
  • Exomes 𝑓: 0.0081 (41 hom.)
• Consequence: MYO1A NM_005379.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1 B:4
• Conservation: PhyloP100: 0.205

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 Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.110271215).
• BP6: Variant 12-57043335-C-T is Benign according to our data. Variant chr12-57043335-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 8148.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-57043335-C-T is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd at 838 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYO1A	NM_005379.4	c.916G>A	p.Val306Met	missense_variant	11/28	ENST00000300119.8
MYO1A	NM_001256041.2	c.916G>A	p.Val306Met	missense_variant	12/29
MYO1A	XM_047428876.1	c.916G>A	p.Val306Met	missense_variant	12/29
MYO1A	XM_011538373.3	c.916G>A	p.Val306Met	missense_variant	11/25

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYO1A	ENST00000300119.8	c.916G>A	p.Val306Met	missense_variant	11/28	1	NM_005379.4	P1
MYO1A	ENST00000442789.6	c.916G>A	p.Val306Met	missense_variant	12/29	1		P1
MYO1A	ENST00000492945.5	c.4G>A	p.Val2Met	missense_variant	3/5	4
MYO1A	ENST00000554234.5	c.430G>A	p.Val144Met	missense_variant, NMD_transcript_variant	7/24	5

Frequencies

GnomAD3 genomes AF: 0.00551 AC: 838 AN: 152182 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.00157

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00465

Gnomad ASJ AF: 0.00519

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00207

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00942

Gnomad OTH AF: 0.00717

GnomAD3 exomes AF: 0.00545 AC: 1369 AN: 251324 Hom.: 7 AF XY: 0.00544 AC XY: 739 AN XY: 135816

Gnomad AFR exome AF: 0.00166

Gnomad AMR exome AF: 0.00289

Gnomad ASJ exome AF: 0.00457

Gnomad EAS exome AF: 0.000163

Gnomad SAS exome AF: 0.00170

Gnomad FIN exome AF: 0.00245

Gnomad NFE exome AF: 0.00931

Gnomad OTH exome AF: 0.00490

GnomAD4 exome AF: 0.00814 AC: 11898 AN: 1461804 Hom.: 41 Cov.: 33 AF XY: 0.00788 AC XY: 5731 AN XY: 727212

Gnomad4 AFR exome AF: 0.00176

Gnomad4 AMR exome AF: 0.00331

Gnomad4 ASJ exome AF: 0.00459

Gnomad4 EAS exome AF: 0.000403

Gnomad4 SAS exome AF: 0.00195

Gnomad4 FIN exome AF: 0.00294

Gnomad4 NFE exome AF: 0.00975

Gnomad4 OTH exome AF: 0.00639

GnomAD4 genome AF: 0.00550 AC: 838 AN: 152300 Hom.: 5 Cov.: 32 AF XY: 0.00512 AC XY: 381 AN XY: 74472

Gnomad4 AFR AF: 0.00156

Gnomad4 AMR AF: 0.00464

Gnomad4 ASJ AF: 0.00519

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00124

Gnomad4 FIN AF: 0.00207

Gnomad4 NFE AF: 0.00942

Gnomad4 OTH AF: 0.00710

Alfa AF: 0.00838 Hom.: 9

Bravo AF: 0.00554

TwinsUK AF: 0.00944 AC: 35

ALSPAC AF: 0.00960 AC: 37

ESP6500AA AF: 0.00159 AC: 7

ESP6500EA AF: 0.00965 AC: 83

ExAC AF: 0.00553 AC: 672

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00862

EpiControl AF: 0.00818

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:1 Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jul 16, 2013	Val306Met in exon 11 of MYO1A: This variant is not expected to have clinical sig nificance because it has been identified in 1% (83/8600) of European American ch romosomes from a broad population by the NHLBI Exome Sequencing Project (http:// evs.gs.washington.edu/EVS/; dbSNP rs55679042) and due to a lack of conservation across species, including mammals. Of note, at least 6 different mammals (rat, mouse, tree shrew, pika, microbat, and wallaby) have a Methionine (Met) at this position despite high nearby amino acid conservation. -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 21, 2014	- -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	MYO1A: BP4, BS2 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 04, 2018	This variant is associated with the following publications: (PMID: 27759032, 25262649, 24616153, 25333069, 12736868) -

Autosomal dominant nonsyndromic hearing loss 48 Uncertain:1

Uncertain significance, no assertion criteria provided

literature only

OMIM

May 01, 2014

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.12
Cadd	Benign	8.2
Dann	Benign	0.76
DEOGEN2	Benign	0.18	T;T;.
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.94
FATHMM_MKL	Benign	0.31	N
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.11	T;T;T
MetaSVM	Benign	-0.76	T
MutationAssessor	Benign	-1.1	N;N;.
MutationTaster	Benign	0.0013	A;A;A
PrimateAI	Benign	0.28	T
PROVEAN	Benign	0.17	N;N;N
REVEL	Uncertain	0.49
Sift	Benign	0.15	T;T;T
Sift4G	Uncertain	0.045	D;D;.
Polyphen		0.0060	B;B;.
Vest4		0.14
MVP		0.60
MPC		0.088
ClinPred		0.0013	T
GERP RS		-1.2
Varity_R		0.066
gMVP		0.22

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: rs55679042; hg19: chr12-57437119;