12-57029150-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_005379.4(MYO1A):c.2987C>T(p.Thr996Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0855 in 1,613,994 control chromosomes in the GnomAD database, including 6,213 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.090 (646 hom., cov: 31)
  • Exomes 𝑓: 0.085 (5567 hom.)
• Consequence: MYO1A NM_005379.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.23

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=0.0014393628).
• BP6: Variant 12-57029150-G-A is Benign according to our data. Variant chr12-57029150-G-A is described in ClinVar as [Benign]. Clinvar id is 45311.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-57029150-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.172 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYO1A	NM_005379.4	c.2987C>T	p.Thr996Ile	missense_variant	27/28	ENST00000300119.8
MYO1A	NM_001256041.2	c.2987C>T	p.Thr996Ile	missense_variant	28/29
MYO1A	XM_047428876.1	c.2987C>T	p.Thr996Ile	missense_variant	28/29

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYO1A	ENST00000300119.8	c.2987C>T	p.Thr996Ile	missense_variant	27/28	1	NM_005379.4	P1
MYO1A	ENST00000442789.6	c.2987C>T	p.Thr996Ile	missense_variant	28/29	1		P1
MYO1A	ENST00000554234.5	c.*432C>T		3_prime_UTR_variant, NMD_transcript_variant	23/24	5

Frequencies

GnomAD3 genomes AF: 0.0897 AC: 13632 AN: 152018 Hom.: 647 Cov.: 31

Gnomad AFR AF: 0.0792

Gnomad AMI AF: 0.0559

Gnomad AMR AF: 0.118

Gnomad ASJ AF: 0.0746

Gnomad EAS AF: 0.182

Gnomad SAS AF: 0.105

Gnomad FIN AF: 0.104

Gnomad MID AF: 0.0570

Gnomad NFE AF: 0.0810

Gnomad OTH AF: 0.0820

GnomAD3 exomes AF: 0.0952 AC: 23903 AN: 251188 Hom.: 1281 AF XY: 0.0950 AC XY: 12902 AN XY: 135742

Gnomad AFR exome AF: 0.0804

Gnomad AMR exome AF: 0.0881

Gnomad ASJ exome AF: 0.0763

Gnomad EAS exome AF: 0.186

Gnomad SAS exome AF: 0.0992

Gnomad FIN exome AF: 0.103

Gnomad NFE exome AF: 0.0841

Gnomad OTH exome AF: 0.0883

GnomAD4 exome AF: 0.0851 AC: 124358 AN: 1461858 Hom.: 5567 Cov.: 33 AF XY: 0.0850 AC XY: 61804 AN XY: 727236

Gnomad4 AFR exome AF: 0.0804

Gnomad4 AMR exome AF: 0.0904

Gnomad4 ASJ exome AF: 0.0742

Gnomad4 EAS exome AF: 0.139

Gnomad4 SAS exome AF: 0.100

Gnomad4 FIN exome AF: 0.102

Gnomad4 NFE exome AF: 0.0813

Gnomad4 OTH exome AF: 0.0851

GnomAD4 genome AF: 0.0896 AC: 13637 AN: 152136 Hom.: 646 Cov.: 31 AF XY: 0.0924 AC XY: 6869 AN XY: 74348

Gnomad4 AFR AF: 0.0791

Gnomad4 AMR AF: 0.118

Gnomad4 ASJ AF: 0.0746

Gnomad4 EAS AF: 0.181

Gnomad4 SAS AF: 0.105

Gnomad4 FIN AF: 0.104

Gnomad4 NFE AF: 0.0810

Gnomad4 OTH AF: 0.0835

Alfa AF: 0.0849 Hom.: 1294

Bravo AF: 0.0891

TwinsUK AF: 0.0771 AC: 286

ALSPAC AF: 0.0786 AC: 303

ESP6500AA AF: 0.0856 AC: 377

ESP6500EA AF: 0.0852 AC: 733

ExAC AF: 0.0944 AC: 11462

Asia WGS AF: 0.133 AC: 460 AN: 3478

EpiCase AF: 0.0773

EpiControl AF: 0.0722

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 07, 2012	Thr996Ile in Exon 27 of MYO1A: This variant is not expected to have clinical sig nificance because it has been identified in 8.6% (605/7020) of European American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http ://evs.gs.washington.edu/EVS; dbSNP rs17119344). -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 09, 2017	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.096
BayesDel_addAF	Benign	-0.73	T
BayesDel_noAF	Benign	-0.67
Cadd	Benign	18
Dann	Benign	0.89
DEOGEN2	Benign	0.067	T;T
Eigen	Benign	-0.71
Eigen_PC	Benign	-0.66
FATHMM_MKL	Benign	0.20	N
MetaRNN	Benign	0.0014	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N;N
MutationTaster	Benign	1.0	P;P;P
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-1.1	N;N
REVEL	Benign	0.029
Sift	Benign	0.20	T;T
Sift4G	Benign	0.20	T;T
Polyphen		0.029	B;B
Vest4		0.076
MPC		0.088
ClinPred		0.0044	T
GERP RS		4.1
Varity_R		0.075
gMVP		0.10

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs17119344; hg19: chr12-57422934; COSMIC: COSV55657629; COSMIC: COSV55657629;