rs151187460

chr12-57037948-G-Achr12-57037948-G-C

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 1P and 8B. PP3 BP4_Moderate BP6_Moderate BS2

The NM_005379.4(MYO1A):c.1882C>T(p.Arg628Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000148 in 1,614,158 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R628G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00015 (2 hom.)
• Consequence: MYO1A NM_005379.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 4.05

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 -7 ACMG points.

• PP3: Multiple lines of computational evidence support a deleterious effect 7: BayesDel_noAF, Cadd, Dann, Eigen, MutationAssessor, PROVEAN, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.21483189).
• BP6: Variant 12-57037948-G-A is Benign according to our data. Variant chr12-57037948-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 514407.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd at 18 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYO1A	NM_005379.4	c.1882C>T	p.Arg628Cys	missense_variant	18/28	ENST00000300119.8
MYO1A	NM_001256041.2	c.1882C>T	p.Arg628Cys	missense_variant	19/29
MYO1A	XM_047428876.1	c.1882C>T	p.Arg628Cys	missense_variant	19/29
MYO1A	XM_011538373.3	c.1882C>T	p.Arg628Cys	missense_variant	18/25

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYO1A	ENST00000300119.8	c.1882C>T	p.Arg628Cys	missense_variant	18/28	1	NM_005379.4	P1
MYO1A	ENST00000442789.6	c.1882C>T	p.Arg628Cys	missense_variant	19/29	1		P1
MYO1A	ENST00000554234.5	c.1396C>T	p.Arg466Cys	missense_variant, NMD_transcript_variant	14/24	5

Frequencies

GnomAD3 genomes AF: 0.000118 AC: 18 AN: 152162 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000982

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: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000657 AC: 165 AN: 251048 Hom.: 1 AF XY: 0.000464 AC XY: 63 AN XY: 135690

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.00469

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: 0.00000882

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000151 AC: 221 AN: 1461878 Hom.: 2 Cov.: 32 AF XY: 0.000125 AC XY: 91 AN XY: 727242

Gnomad4 AFR exome AF: 0.000119

Gnomad4 AMR exome AF: 0.00396

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000315

Gnomad4 OTH exome AF: 0.0000662

GnomAD4 genome AF: 0.000118 AC: 18 AN: 152280 Hom.: 0 Cov.: 32 AF XY: 0.000121 AC XY: 9 AN XY: 74452

Gnomad4 AFR AF: 0.0000722

Gnomad4 AMR AF: 0.000981

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000341 Hom.: 0

Bravo AF: 0.000283

ExAC AF: 0.000544 AC: 66

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 04, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.53
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Pathogenic	0.43
Cadd	Pathogenic	31
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.86	D;D
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Uncertain	0.97	D
M_CAP	Uncertain	0.17	D
MetaRNN	Benign	0.21	T;T
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.4	H;H
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.59	T
PROVEAN	Pathogenic	-7.8	D;D
REVEL	Pathogenic	0.81
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.93
MVP		0.97
MPC		0.53
ClinPred		0.26	T
GERP RS		5.1
Varity_R		0.83
gMVP		0.71

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs151187460; hg19: chr12-57431732; COSMIC: COSV55657173; COSMIC: COSV55657173;