Genetic Variant MYO1A:p.Pro426Gln (chr12-57039267-G-T) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_005379.4(MYO1A):c.1277C>A(p.Pro426Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,456 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P426L) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

MYO1A
NM_005379.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.71

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

nonsyndromic genetic hearing loss
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

MYO1A links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.3458283).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
MYO1A	NM_005379.4 link	c.1277C>A	p.Pro426Gln	missense_variant	Exon 15 of 28	ENST00000300119.8	NP_005370.1
MYO1A	NM_001256041.2 link	c.1277C>A	p.Pro426Gln	missense_variant	Exon 16 of 29		NP_001242970.1
MYO1A	XM_047428876.1 link	c.1277C>A	p.Pro426Gln	missense_variant	Exon 16 of 29		XP_047284832.1
MYO1A	XM_011538373.3 link	c.1277C>A	p.Pro426Gln	missense_variant	Exon 15 of 25		XP_011536675.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
MYO1A	ENST00000300119.8 link	c.1277C>A	p.Pro426Gln	missense_variant	Exon 15 of 28	1	NM_005379.4	ENSP00000300119.3
MYO1A	ENST00000442789.6 link	c.1277C>A	p.Pro426Gln	missense_variant	Exon 16 of 29	1		ENSP00000393392.2
MYO1A	ENST00000476795.1 link	n.174C>A		non_coding_transcript_exon_variant	Exon 1 of 3	5
MYO1A	ENST00000554234.5 link	n.791C>A		non_coding_transcript_exon_variant	Exon 11 of 24	5		ENSP00000451033.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461456

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727054

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33474

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26130

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86238

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53404

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111638

Other (OTH)

AF:

0.00

AC:

AN:

60380

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Uncertain

0.016

BayesDel_noAF

Benign

-0.22

CADD

Benign

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.13

T;T

Eigen

Benign

-0.14

Eigen_PC

Benign

-0.0098

FATHMM_MKL

Uncertain

0.79

LIST_S2

Benign

0.85

.;T

M_CAP

Benign

0.035

MetaRNN

Benign

0.35

T;T

MetaSVM

Benign

-0.37

MutationAssessor

Benign

-0.30

N;N

PhyloP100

2.7

PrimateAI

Benign

0.40

PROVEAN

Benign

0.58

N;N

REVEL

Benign

0.27

Sift

Benign

0.15

T;T

Sift4G

Benign

0.21

T;T

Polyphen

0.48

P;P

Vest4

0.17

MutPred

0.33

Loss of catalytic residue at W427 (P = 0.0373);Loss of catalytic residue at W427 (P = 0.0373);

MVP

0.78

MPC

0.092

ClinPred

0.80

GERP RS

3.8

Varity_R

0.10

gMVP

0.18

Mutation Taster

=98/2

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.10

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over