rs200450661

Positions:

• chr12-57037902-C-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_005379.4(MYO1A):​c.1928G>A​(p.Arg643Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000403 in 1,614,152 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000040 (0 hom.)
• Consequence: MYO1A NM_005379.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.677

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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.059339494).
• BP6: Variant 12-57037902-C-T is Benign according to our data. Variant chr12-57037902-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 164589.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd4 at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYO1A	NM_005379.4	c.1928G>A	p.Arg643Gln	missense_variant	18/28	ENST00000300119.8
MYO1A	NM_001256041.2	c.1928G>A	p.Arg643Gln	missense_variant	19/29
MYO1A	XM_047428876.1	c.1928G>A	p.Arg643Gln	missense_variant	19/29
MYO1A	XM_011538373.3	c.1928G>A	p.Arg643Gln	missense_variant	18/25

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYO1A	ENST00000300119.8	c.1928G>A	p.Arg643Gln	missense_variant	18/28	1	NM_005379.4	P1
MYO1A	ENST00000442789.6	c.1928G>A	p.Arg643Gln	missense_variant	19/29	1		P1
MYO1A	ENST00000554234.5	c.1442G>A	p.Arg481Gln	missense_variant, NMD_transcript_variant	14/24	5

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152172 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000319 AC: 8 AN: 250974 Hom.: 0 AF XY: 0.0000221 AC XY: 3 AN XY: 135660

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000617

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000397 AC: 58 AN: 1461862 Hom.: 0 Cov.: 33 AF XY: 0.0000371 AC XY: 27 AN XY: 727228

Gnomad4 AFR exome AF: 0.000448

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000306

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome AF: 0.0000460 AC: 7 AN: 152290 Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3 AN XY: 74460

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000823 Hom.: 0

Bravo AF: 0.0000491

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000247 AC: 3

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Nov 18, 2014

p.Arg643Gln in exon 18 of MYO1A: This variant is not expected to have clinical significance because the arginine (Arg) residue at position 643 is not conserved in mammals or across species, with guinea pig and rabbit having a glutamine (Gl n). In addition, recent evidence has disqualified an association between variant s in the MYO1A gene and hearing loss (Eisenberger 2014). This variant has also been identified in 0.5% (1/192) of Kenyan chromosomes by the 1000 Genomes Projec t (rs200450661). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Benign	0.19	T;T
Eigen	Benign	-0.53
Eigen_PC	Benign	-0.44
FATHMM_MKL	Benign	0.21	N
M_CAP	Benign	0.033	D
MetaRNN	Benign	0.059	T;T
MetaSVM	Benign	-0.52	T
MutationAssessor	Benign	0.89	L;L
MutationTaster	Benign	0.80	D;D;D
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-0.69	N;N
REVEL	Benign	0.19
Sift	Benign	0.21	T;T
Sift4G	Benign	0.34	T;T
Polyphen		0.016	B;B
Vest4		0.18
MVP		0.74
MPC		0.096
ClinPred		0.049	T
GERP RS		2.3
Varity_R		0.096
gMVP		0.20

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		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: rs200450661; hg19: chr12-57431686;