rs370708976

Positions:

chr12-57029217-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_005379.4(MYO1A):c.2920G>A(p.Glu974Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000395 in 1,614,166 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00030 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00040 ( 5 hom. )

Consequence

MYO1A
NM_005379.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: 1.63

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.011177957).

BP6

Variant 12-57029217-C-T is Benign according to our data. Variant chr12-57029217-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 178845.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

BS2

High AC in GnomAd4 at 45 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
MYO1A	NM_005379.4 linkuse as main transcript	c.2920G>A	p.Glu974Lys	missense_variant	27/28	ENST00000300119.8	NP_005370.1
MYO1A	NM_001256041.2 linkuse as main transcript	c.2920G>A	p.Glu974Lys	missense_variant	28/29		NP_001242970.1
MYO1A	XM_047428876.1 linkuse as main transcript	c.2920G>A	p.Glu974Lys	missense_variant	28/29		XP_047284832.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
MYO1A	ENST00000300119.8 linkuse as main transcript	c.2920G>A	p.Glu974Lys	missense_variant	27/28	1	NM_005379.4	ENSP00000300119	P1
MYO1A	ENST00000442789.6 linkuse as main transcript	c.2920G>A	p.Glu974Lys	missense_variant	28/29	1		ENSP00000393392	P1
MYO1A	ENST00000554234.5 linkuse as main transcript	c.*365G>A		3_prime_UTR_variant, NMD_transcript_variant	23/24	5		ENSP00000451033

Frequencies

GnomAD3 genomes

AF:

0.000296

AC:

AN:

152168

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00932

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000789

AC:

198

AN:

251072

Hom.:

AF XY:

0.00108

AC XY:

147

AN XY:

135682

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00640

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.000405

AC:

592

AN:

1461880

Hom.:

Cov.:

AF XY:

0.000575

AC XY:

418

AN XY:

727240

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00647

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000989

Gnomad4 OTH exome

AF:

0.000331

GnomAD4 genome

AF:

0.000295

AC:

AN:

152286

Hom.:

Cov.:

AF XY:

0.000470

AC XY:

AN XY:

74466

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00933

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000854

Hom.:

Bravo

AF:

0.0000378

ExAC

AF:

0.000939

AC:

114

Asia WGS

AF:

0.00144

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Apr 04, 2013

Variant classified as Uncertain Significance - Favor Benign. The Glu974Lys varia nt in MYO1A has not been reported in individuals affected with hearing loss or i n large population studies. Computational analyses (biochemical amino acid prope rties, conservation, AlignGVGD, PolyPhen2, and SIFT) suggest that the Glu974Lys variant may not impact the protein, though this information is not predictive en ough to rule out pathogenicity. In summary, the clinical significance of this va riant cannot be determined with certainty; however, based upon low conservation and computational predictions, we lean towards a more likely benign role. -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Sep 09, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.089

BayesDel_addAF

Benign

-0.52

BayesDel_noAF

Benign

-0.52

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.049

T;T

Eigen

Benign

-0.19

Eigen_PC

Benign

-0.076

FATHMM_MKL

Uncertain

0.87

LIST_S2

Benign

0.59

.;T

MetaRNN

Benign

0.011

T;T

MetaSVM

Benign

-0.95

MutationAssessor

Uncertain

2.2

M;M

MutationTaster

Benign

0.55

N;N;N

PrimateAI

Benign

0.37

PROVEAN

Benign

-1.3

N;N

REVEL

Benign

0.033

Sift

Benign

0.32

T;T

Sift4G

Benign

0.65

T;T

Polyphen

0.11

B;B

Vest4

0.28

MutPred

0.64

Gain of ubiquitination at E974 (P = 0.0192);Gain of ubiquitination at E974 (P = 0.0192);

MVP

0.66

MPC

0.096

ClinPred

0.089

GERP RS

4.2

Varity_R

0.11

gMVP

0.30

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over