rs146373415

chr12-57029756-T-C

Variant summary

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

The NM_005379.4(MYO1A):c.2708A>G(p.Asn903Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000164 in 1,614,200 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00019 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00016 (0 hom.)
• Consequence: MYO1A NM_005379.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.94

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 GnomAd at 29 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYO1A	NM_005379.4	c.2708A>G	p.Asn903Ser	missense_variant	25/28	ENST00000300119.8
MYO1A	NM_001256041.2	c.2708A>G	p.Asn903Ser	missense_variant	26/29
MYO1A	XM_047428876.1	c.2708A>G	p.Asn903Ser	missense_variant	26/29

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYO1A	ENST00000300119.8	c.2708A>G	p.Asn903Ser	missense_variant	25/28	1	NM_005379.4	P1
MYO1A	ENST00000442789.6	c.2708A>G	p.Asn903Ser	missense_variant	26/29	1		P1
MYO1A	ENST00000477864.1	n.271A>G		non_coding_transcript_exon_variant	3/4	2
MYO1A	ENST00000554234.5	c.*153A>G		3_prime_UTR_variant, NMD_transcript_variant	21/24	5

Frequencies

GnomAD3 genomes AF: 0.000191 AC: 29 AN: 152188 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000524

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.000955

GnomAD3 exomes AF: 0.000227 AC: 57 AN: 251388 Hom.: 0 AF XY: 0.000213 AC XY: 29 AN XY: 135860

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.000549

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.000686

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000114

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000161 AC: 236 AN: 1461894 Hom.: 0 Cov.: 33 AF XY: 0.000166 AC XY: 121 AN XY: 727248

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.000470

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.000696

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000112

Gnomad4 OTH exome AF: 0.000348

GnomAD4 genome AF: 0.000190 AC: 29 AN: 152306 Hom.: 0 Cov.: 32 AF XY: 0.000148 AC XY: 11 AN XY: 74486

Gnomad4 AFR AF: 0.000144

Gnomad4 AMR AF: 0.000523

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000132

Gnomad4 OTH AF: 0.000945

Alfa AF: 0.000195 Hom.: 0

Bravo AF: 0.000280

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000173 AC: 21

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000491

EpiControl AF: 0.000415

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Oct 16, 2014

The p.Asn903Ser variant in MYO1A has not been reported in individuals with heari ng loss, but has been identified in 0.012% (1/8600) of European American chromos omes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/; d bSNP rs146373415). Although this variant has been seen in the general population , its frequency is not high enough to rule out a pathogenic role. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, the clinical significance of the p.Asn903Ser variant is uncertain. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.46
Cadd	Pathogenic	33
Dann	Uncertain	1.0
DEOGEN2	Benign	0.28	T;T
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Benign	0.028	D
MetaRNN	Uncertain	0.51	D;D
MetaSVM	Benign	-0.78	T
MutationAssessor	Pathogenic	3.1	M;M
MutationTaster	Benign	0.94	D;D;D
PrimateAI	Uncertain	0.53	T
PROVEAN	Uncertain	-2.8	D;D
REVEL	Benign	0.20
Sift	Uncertain	0.011	D;D
Sift4G	Uncertain	0.047	D;D
Polyphen		0.67	P;P
Vest4		0.69
MVP		0.69
MPC		0.37
ClinPred		0.45	T
GERP RS		3.5
Varity_R		0.25
gMVP		0.30

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.74		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.74		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: rs146373415; hg19: chr12-57423540;