rs12297756

chr12-57038825-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_005379.4(MYO1A):c.1517G>C(p.Cys506Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0014 in 1,614,192 control chromosomes in the GnomAD database, including 25 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.0072 (17 hom., cov: 32)
  • Exomes 𝑓: 0.00079 (8 hom.)
• Consequence: MYO1A NM_005379.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 2.82

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010234833).
• BP6: Variant 12-57038825-C-G is Benign according to our data. Variant chr12-57038825-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 164594.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00725 (1104/152306) while in subpopulation AFR AF= 0.0248 (1032/41560). AF 95% confidence interval is 0.0236. There are 17 homozygotes in gnomad4. There are 528 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 1102 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYO1A	NM_005379.4	c.1517G>C	p.Cys506Ser	missense_variant	16/28	ENST00000300119.8
MYO1A	NM_001256041.2	c.1517G>C	p.Cys506Ser	missense_variant	17/29
MYO1A	XM_047428876.1	c.1517G>C	p.Cys506Ser	missense_variant	17/29
MYO1A	XM_011538373.3	c.1517G>C	p.Cys506Ser	missense_variant	16/25

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYO1A	ENST00000300119.8	c.1517G>C	p.Cys506Ser	missense_variant	16/28	1	NM_005379.4	P1
MYO1A	ENST00000442789.6	c.1517G>C	p.Cys506Ser	missense_variant	17/29	1		P1
MYO1A	ENST00000476795.1	n.414G>C		non_coding_transcript_exon_variant	2/3	5
MYO1A	ENST00000554234.5	c.1031G>C	p.Cys344Ser	missense_variant, NMD_transcript_variant	12/24	5

Frequencies

GnomAD3 genomes AF: 0.00724 AC: 1102 AN: 152188 Hom.: 17 Cov.: 32

Gnomad AFR AF: 0.0249

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00366

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00430

GnomAD3 exomes AF: 0.00204 AC: 512 AN: 251108 Hom.: 7 AF XY: 0.00147 AC XY: 200 AN XY: 135706

Gnomad AFR exome AF: 0.0269

Gnomad AMR exome AF: 0.00171

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000882

Gnomad OTH exome AF: 0.000979

GnomAD4 exome AF: 0.000791 AC: 1157 AN: 1461886 Hom.: 8 Cov.: 32 AF XY: 0.000682 AC XY: 496 AN XY: 727244

Gnomad4 AFR exome AF: 0.0258

Gnomad4 AMR exome AF: 0.00188

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000719

Gnomad4 OTH exome AF: 0.00189

GnomAD4 genome AF: 0.00725 AC: 1104 AN: 152306 Hom.: 17 Cov.: 32 AF XY: 0.00709 AC XY: 528 AN XY: 74464

Gnomad4 AFR AF: 0.0248

Gnomad4 AMR AF: 0.00366

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.00426

Alfa AF: 0.00116 Hom.: 2

Bravo AF: 0.00835

ESP6500AA AF: 0.0202 AC: 89

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00233 AC: 283

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.0000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Dec 31, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 31, 2018	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

May 07, 2012

Cys506Ser in Exon 16 of MYO1A: This variant is not expected to have clinical sig nificance because it has been identified in 2.0% (76/3738) of African American c hromosomes from a broad population by the NHLBI Exome Sequencing Project (http:/ /evs.gs.washington.edu/EVS; dbSNP rs12297756). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.41
Cadd	Benign	18
Dann	Benign	0.69
DEOGEN2	Benign	0.14	T;T
Eigen	Benign	-0.56
Eigen_PC	Benign	-0.37
FATHMM_MKL	Uncertain	0.87	D
MetaRNN	Benign	0.010	T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	-0.22	N;N
MutationTaster	Benign	0.88	N;N;N
PrimateAI	Benign	0.30	T
PROVEAN	Benign	1.0	N;N
REVEL	Benign	0.14
Sift	Benign	0.53	T;T
Sift4G	Benign	0.83	T;T
Polyphen		0.0	B;B
Vest4		0.15
MutPred		0.26		Gain of catalytic residue at C506 (P = 0.0456);Gain of catalytic residue at C506 (P = 0.0456);
MVP		0.49
MPC		0.10
ClinPred		0.015	T
GERP RS		1.6
Varity_R		0.063
gMVP		0.30

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs12297756; hg19: chr12-57432609; COSMIC: COSV99037935; COSMIC: COSV99037935;