12-57029150-G-A

Variant names:

• chr12-57029150-G-A
• rs17119344
• NM_005379.4:c.2987C>T

Variant summary

Our verdict is Benign. The variant received -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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• 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:4
• Conservation: PhyloP100: 1.23
• Publications: 24 publications found

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]

MYO1A Gene-Disease associations (from GenCC):

• nonsyndromic genetic hearing loss

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 45311.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.172 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005379.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYO1A	NM_005379.4	MANE Select	c.2987C>T	p.Thr996Ile	missense	Exon 27 of 28	NP_005370.1
	MYO1A	NM_001256041.2		c.2987C>T	p.Thr996Ile	missense	Exon 28 of 29	NP_001242970.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYO1A	ENST00000300119.8	TSL:1 MANE Select	c.2987C>T	p.Thr996Ile	missense	Exon 27 of 28	ENSP00000300119.3
	MYO1A	ENST00000442789.6	TSL:1	c.2987C>T	p.Thr996Ile	missense	Exon 28 of 29	ENSP00000393392.2
	MYO1A	ENST00000554234.5	TSL:5	n.*432C>T		non_coding_transcript_exon	Exon 23 of 24	ENSP00000451033.1

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

GnomAD2 exomes AF: 0.0952 AC: 23903 AN: 251188 AF XY: 0.0950

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 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

African (AFR) AF: 0.0804 AC: 2692 AN: 33480

American (AMR) AF: 0.0904 AC: 4041 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0742 AC: 1939 AN: 26134

East Asian (EAS) AF: 0.139 AC: 5528 AN: 39700

South Asian (SAS) AF: 0.100 AC: 8650 AN: 86258

European-Finnish (FIN) AF: 0.102 AC: 5458 AN: 53416

Middle Eastern (MID) AF: 0.0884 AC: 510 AN: 5768

European-Non Finnish (NFE) AF: 0.0813 AC: 90402 AN: 1111984

Other (OTH) AF: 0.0851 AC: 5138 AN: 60394

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

African (AFR) AF: 0.0791 AC: 3283 AN: 41528

American (AMR) AF: 0.118 AC: 1803 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.0746 AC: 259 AN: 3470

East Asian (EAS) AF: 0.181 AC: 937 AN: 5166

South Asian (SAS) AF: 0.105 AC: 507 AN: 4814

European-Finnish (FIN) AF: 0.104 AC: 1098 AN: 10570

Middle Eastern (MID) AF: 0.0510 AC: 15 AN: 294

European-Non Finnish (NFE) AF: 0.0810 AC: 5508 AN: 67992

Other (OTH) AF: 0.0835 AC: 176 AN: 2108

Alfa AF: 0.0851 Hom.: 1866

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:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

May 09, 2017

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

May 07, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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).

not provided Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-0.71
Eigen_PC	Benign	-0.66
FATHMM_MKL	Benign	0.20	N
LIST_S2	Benign	0.10	T
MetaRNN	Benign	0.0014	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N
PhyloP100		1.2
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.029
Sift	Benign	0.20	T
Sift4G	Benign	0.20	T
Polyphen		0.029	B
Vest4		0.076
MPC		0.088
ClinPred		0.0044	T
GERP RS		4.1
PromoterAI		-0.026	Neutral
Varity_R		0.075
gMVP		0.10
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

dbSNP: rs17119344; hg19: chr12-57422934; COSMIC: COSV55657629; COSMIC: COSV55657629;