rs113470661

Positions:

• chr12-57031134-G-A

Variant summary

Our verdict is Benign. Variant got -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 (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• 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

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 -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 [Likely_benign]. Clinvar id is 178620.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-57031134-G-A is described in Lovd as [Benign].
• BS2: High AC in GnomAd4 at 742 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYO1A	NM_005379.4	c.2390C>T	p.Ser797Phe	missense_variant	23/28	ENST00000300119.8
MYO1A	NM_001256041.2	c.2390C>T	p.Ser797Phe	missense_variant	24/29
MYO1A	XM_047428876.1	c.2390C>T	p.Ser797Phe	missense_variant	24/29
MYO1A	XM_011538373.3	c.2390C>T	p.Ser797Phe	missense_variant	23/25

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYO1A	ENST00000300119.8	c.2390C>T	p.Ser797Phe	missense_variant	23/28	1	NM_005379.4	P1

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

GnomAD3 exomes AF: 0.00451 AC: 1135 AN: 251450 Hom.: 2 AF XY: 0.00433 AC XY: 588 AN XY: 135904

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 SAS exome AF: 0.000555

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

Gnomad4 AFR exome AF: 0.000806

Gnomad4 AMR exome AF: 0.00143

Gnomad4 ASJ exome AF: 0.00218

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000487

Gnomad4 FIN exome AF: 0.00796

Gnomad4 NFE exome AF: 0.00716

Gnomad4 OTH exome AF: 0.00576

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

Gnomad4 AFR AF: 0.00120

Gnomad4 AMR AF: 0.00111

Gnomad4 ASJ AF: 0.00260

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00838

Gnomad4 NFE AF: 0.00839

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00683 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

Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 07, 2012	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). -
Benign, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Jul 30, 2015	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 01, 2017	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 23, 2021	This variant is associated with the following publications: (PMID: 24875298, 25262649, 24616153, 12736868) -
Benign, criteria provided, single submitter	clinical testing	Invitae	Dec 10, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2023	MYO1A: BP4, BS2 -

Computational scores

Source: dbNSFP v4.3

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;T
Eigen	Benign	0.16
Eigen_PC	Benign	0.15
FATHMM_MKL	Uncertain	0.96	D
MetaRNN	Benign	0.0074	T;T
MetaSVM	Uncertain	0.19	D
MutationAssessor	Pathogenic	2.9	M;M
MutationTaster	Benign	0.93	D;D;D
PrimateAI	Benign	0.34	T
PROVEAN	Uncertain	-4.1	D;D
REVEL	Pathogenic	0.67
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.0050	D;D
Polyphen		0.44	B;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

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

Publications

LitVar

Other links and lift over

dbSNP: rs113470661; hg19: chr12-57424918;