chr12-57031134-G-A

Variant names:

• chr12-57031134-G-A
• rs113470661
• NM_005379.4:c.2390C>T

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_005379.4(MYO1A):​c.2390C>T​(p.Ser797Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00599 in 1,614,148 control chromosomes in the GnomAD database, including 37 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0049 (5 hom., cov: 32)
  • Exomes 𝑓: 0.0061 (32 hom.)
• Consequence: MYO1A NM_005379.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 8.02
• Publications: 22 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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0073539317).
• BP6: Variant 12-57031134-G-A is Benign according to our data. Variant chr12-57031134-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 178620.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 742 AD gene.

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.2390C>T	p.Ser797Phe	missense	Exon 23 of 28	NP_005370.1
	MYO1A	NM_001256041.2		c.2390C>T	p.Ser797Phe	missense	Exon 24 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.2390C>T	p.Ser797Phe	missense	Exon 23 of 28	ENSP00000300119.3
	MYO1A	ENST00000442789.6	TSL:1	c.2390C>T	p.Ser797Phe	missense	Exon 24 of 29	ENSP00000393392.2
	MYO1A	ENST00000554234.5	TSL:5	n.1904C>T		non_coding_transcript_exon	Exon 19 of 24	ENSP00000451033.1

Frequencies

GnomAD3 genomes AF: 0.00488 AC: 742 AN: 152150 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.00121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00111

Gnomad ASJ AF: 0.00260

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00838

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00839

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.00451 AC: 1135 AN: 251450 AF XY: 0.00433

Gnomad AFR exome AF: 0.000800

Gnomad AMR exome AF: 0.00142

Gnomad ASJ exome AF: 0.00278

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00868

Gnomad NFE exome AF: 0.00711

Gnomad OTH exome AF: 0.00505

GnomAD4 exome AF: 0.00611 AC: 8931 AN: 1461880 Hom.: 32 Cov.: 32 AF XY: 0.00600 AC XY: 4367 AN XY: 727244

African (AFR) AF: 0.000806 AC: 27 AN: 33480

American (AMR) AF: 0.00143 AC: 64 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00218 AC: 57 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000487 AC: 42 AN: 86258

European-Finnish (FIN) AF: 0.00796 AC: 425 AN: 53420

Middle Eastern (MID) AF: 0.000693 AC: 4 AN: 5768

European-Non Finnish (NFE) AF: 0.00716 AC: 7964 AN: 1112000

Other (OTH) AF: 0.00576 AC: 348 AN: 60396

GnomAD4 genome AF: 0.00487 AC: 742 AN: 152268 Hom.: 5 Cov.: 32 AF XY: 0.00479 AC XY: 357 AN XY: 74458

African (AFR) AF: 0.00120 AC: 50 AN: 41534

American (AMR) AF: 0.00111 AC: 17 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00260 AC: 9 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4824

European-Finnish (FIN) AF: 0.00838 AC: 89 AN: 10624

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00839 AC: 571 AN: 68022

Other (OTH) AF: 0.00189 AC: 4 AN: 2112

Alfa AF: 0.00643 Hom.: 5

Bravo AF: 0.00374

TwinsUK AF: 0.00512 AC: 19

ALSPAC AF: 0.00519 AC: 20

ESP6500AA AF: 0.00113 AC: 5

ESP6500EA AF: 0.00733 AC: 63

ExAC AF: 0.00466 AC: 566

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00785

EpiControl AF: 0.00575

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

May 07, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Ser797Phe in Exon 23 of MYO1A: This variant is not expected to have clinical sig nificance because it has been identified in 0.7% (47/7020) of European American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http: //evs.gs.washington.edu/EVS; dbSNP rs113470661).

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Jun 01, 2017

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jul 30, 2015

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:3

Feb 23, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 24875298, 25262649, 24616153, 12736868)

Dec 10, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Oct 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

MYO1A: BP4, BS2

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.055	T
BayesDel_noAF	Pathogenic	0.16
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.37	T
Eigen	Benign	0.16
Eigen_PC	Benign	0.15
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.79	T
MetaRNN	Benign	0.0074	T
MetaSVM	Uncertain	0.19	D
MutationAssessor	Pathogenic	2.9	M
PhyloP100		8.0
PrimateAI	Benign	0.34	T
PROVEAN	Uncertain	-4.1	D
REVEL	Pathogenic	0.67
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0050	D
Polyphen		0.44	B
Vest4		0.43
MVP		0.86
MPC		0.32
ClinPred		0.045	T
GERP RS		4.2
Varity_R		0.32
gMVP		0.17
Mutation Taster		=93/7	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs113470661; hg19: chr12-57424918;