rs144384395

chr12-57036315-T-C

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_005379.4(MYO1A):c.2341A>G(p.Lys781Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00137 in 1,613,606 control chromosomes in the GnomAD database, including 4 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0010 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0014 (4 hom.)
• Consequence: MYO1A NM_005379.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 0.680

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.011663854).
• BP6: Variant 12-57036315-T-C is Benign according to our data. Variant chr12-57036315-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 164583.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=1}. Variant chr12-57036315-T-C is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd at 153 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYO1A	NM_005379.4	c.2341A>G	p.Lys781Glu	missense_variant	22/28	ENST00000300119.8
MYO1A	NM_001256041.2	c.2341A>G	p.Lys781Glu	missense_variant	23/29
MYO1A	XM_047428876.1	c.2341A>G	p.Lys781Glu	missense_variant	23/29
MYO1A	XM_011538373.3	c.2341A>G	p.Lys781Glu	missense_variant	22/25

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYO1A	ENST00000300119.8	c.2341A>G	p.Lys781Glu	missense_variant	22/28	1	NM_005379.4	P1
MYO1A	ENST00000442789.6	c.2341A>G	p.Lys781Glu	missense_variant	23/29	1		P1
MYO1A	ENST00000554234.5	c.1855A>G	p.Lys619Glu	missense_variant, NMD_transcript_variant	18/24	5

Frequencies

GnomAD3 genomes AF: 0.00101 AC: 153 AN: 152160 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00183

Gnomad ASJ AF: 0.00461

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00147

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.000796 AC: 200 AN: 251146 Hom.: 0 AF XY: 0.000884 AC XY: 120 AN XY: 135716

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000983

Gnomad ASJ exome AF: 0.00337

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00107

Gnomad OTH exome AF: 0.000979

GnomAD4 exome AF: 0.00141 AC: 2057 AN: 1461446 Hom.: 4 Cov.: 32 AF XY: 0.00134 AC XY: 976 AN XY: 727030

Gnomad4 AFR exome AF: 0.000179

Gnomad4 AMR exome AF: 0.00132

Gnomad4 ASJ exome AF: 0.00383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000104

Gnomad4 FIN exome AF: 0.0000374

Gnomad4 NFE exome AF: 0.00159

Gnomad4 OTH exome AF: 0.00186

GnomAD4 genome AF: 0.00101 AC: 153 AN: 152160 Hom.: 0 Cov.: 32 AF XY: 0.00106 AC XY: 79 AN XY: 74330

Gnomad4 AFR AF: 0.0000965

Gnomad4 AMR AF: 0.00183

Gnomad4 ASJ AF: 0.00461

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000943

Gnomad4 NFE AF: 0.00147

Gnomad4 OTH AF: 0.00191

Alfa AF: 0.00127 Hom.: 0

Bravo AF: 0.00110

TwinsUK AF: 0.00162 AC: 6

ALSPAC AF: 0.00234 AC: 9

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00233 AC: 20

ExAC AF: 0.000692 AC: 84

EpiCase AF: 0.00153

EpiControl AF: 0.00119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1 Benign:3

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 18, 2021	The c.2341A>G (p.K781E) alteration is located in exon 22 (coding exon 21) of the MYO1A gene. This alteration results from a A to G substitution at nucleotide position 2341, causing the lysine (K) at amino acid position 781 to be replaced by a glutamic acid (E). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 02, 2018	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. -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 01, 2014	Lys781Glu in exon 22 of MYO1A: This variant is not expected to have clinical sig nificance because it has been identified in 0.23% (20/8600) of European American chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu ; dbSNP rs144384395). In addition, lysine (Lys) is not well conserved in mammals and across evolutionary distant species, and several computational prediction t ools suggest this variant may not impact the protein. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.29
Cadd	Benign	17
Dann	Benign	0.93
DEOGEN2	Benign	0.042	T;T
Eigen	Benign	-0.68
Eigen_PC	Benign	-0.57
FATHMM_MKL	Benign	0.10	N
M_CAP	Benign	0.032	D
MetaRNN	Benign	0.012	T;T
MetaSVM	Benign	-0.78	T
MutationAssessor	Uncertain	2.2	M;M
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.43	N;N
REVEL	Benign	0.22
Sift	Benign	0.37	T;T
Sift4G	Benign	0.30	T;T
Polyphen		0.020	B;B
Vest4		0.30
MVP		0.68
MPC		0.12
ClinPred		0.013	T
GERP RS		2.2
Varity_R		0.071
gMVP		0.23

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

Other links and lift over

dbSNP: rs144384395; hg19: chr12-57430099; COSMIC: COSV99037929; COSMIC: COSV99037929;