12-57028861-T-G

Position:

• chr12-57028861-T-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_005379.4(MYO1A):​c.3026A>C​(p.Glu1009Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00362 in 1,613,388 control chromosomes in the GnomAD database, including 190 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.019 (100 hom., cov: 31)
  • Exomes 𝑓: 0.0020 (90 hom.)
• Consequence: MYO1A NM_005379.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 3.19

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]

TAC3 (HGNC:11521): (tachykinin precursor 3) This gene encodes a member of the tachykinin family of secreted neuropeptides. The encoded preproprotein is proteolytically processed to generate the mature peptide, which is primarily expressed in the central and peripheral nervous systems and functions as a neurotransmitter. This peptide is the ligand for the neurokinin-3 receptor. This protein is also expressed in the outer syncytiotrophoblast of the placenta and may be associated with pregnancy-induced hypertension and pre-eclampsia. Mutations in this gene are associated with normosmic hypogonadotropic hypogonadism. Alternative splicing results in multiple transcript variants, at least one of which encodes an isoform that is proteolytically processed. [provided by RefSeq, Feb 2016]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.002011478).
• BP6: Variant 12-57028861-T-G is Benign according to our data. Variant chr12-57028861-T-G is described in ClinVar as [Benign]. Clinvar id is 178621.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0631 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYO1A	NM_005379.4	c.3026A>C	p.Glu1009Ala	missense_variant	28/28	ENST00000300119.8	NP_005370.1
MYO1A	NM_001256041.2	c.3026A>C	p.Glu1009Ala	missense_variant	29/29		NP_001242970.1
MYO1A	XM_047428876.1	c.3026A>C	p.Glu1009Ala	missense_variant	29/29		XP_047284832.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYO1A	ENST00000300119.8	c.3026A>C	p.Glu1009Ala	missense_variant	28/28	1	NM_005379.4	ENSP00000300119	P1
MYO1A	ENST00000442789.6	c.3026A>C	p.Glu1009Ala	missense_variant	29/29	1		ENSP00000393392	P1
TAC3	ENST00000415231.1	c.-199A>C		5_prime_UTR_variant	1/7	5		ENSP00000402995	P1
MYO1A	ENST00000554234.5	c.*471A>C		3_prime_UTR_variant, NMD_transcript_variant	24/24	5		ENSP00000451033

Frequencies

GnomAD3 genomes AF: 0.0189 AC: 2875 AN: 151994 Hom.: 100 Cov.: 31

Gnomad AFR AF: 0.0651

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00871

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000624

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.0163

GnomAD3 exomes AF: 0.00484 AC: 1205 AN: 249010 Hom.: 41 AF XY: 0.00358 AC XY: 482 AN XY: 134782

Gnomad AFR exome AF: 0.0653

Gnomad AMR exome AF: 0.00281

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000251

Gnomad OTH exome AF: 0.00245

GnomAD4 exome AF: 0.00202 AC: 2948 AN: 1461276 Hom.: 90 Cov.: 31 AF XY: 0.00175 AC XY: 1272 AN XY: 726948

Gnomad4 AFR exome AF: 0.0698

Gnomad4 AMR exome AF: 0.00362

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000209

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000927

Gnomad4 OTH exome AF: 0.00499

GnomAD4 genome AF: 0.0190 AC: 2886 AN: 152112 Hom.: 100 Cov.: 31 AF XY: 0.0188 AC XY: 1401 AN XY: 74358

Gnomad4 AFR AF: 0.0652

Gnomad4 AMR AF: 0.00870

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000416

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000147

Gnomad4 OTH AF: 0.0161

Alfa AF: 0.00346 Hom.: 13

Bravo AF: 0.0217

ESP6500AA AF: 0.0606 AC: 267

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00570 AC: 692

Asia WGS AF: 0.00346 AC: 12 AN: 3478

EpiCase AF: 0.000327

EpiControl AF: 0.000356

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 01, 2017	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. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 07, 2012	Glu1009Ala in Exon 28 of MYO1A: This variant is not expected to have clinical si gnificance because it has been identified in 6.3% (235/3738) of African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http ://evs.gs.washington.edu/EVS; dbSNP rs76394585). -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Benign	0.039	T;T
Eigen	Benign	0.13
Eigen_PC	Benign	0.13
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.74	.;T
MetaRNN	Benign	0.0020	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.1	M;M
MutationTaster	Benign	1.0	N;N;N;D
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.93	N;N
REVEL	Benign	0.12
Sift	Benign	0.22	T;T
Sift4G	Benign	0.40	T;T
Polyphen		0.80	P;P
Vest4		0.15
MVP		0.64
MPC		0.090
ClinPred		0.020	T
GERP RS		4.0
Varity_R		0.077
gMVP		0.30

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: rs76394585; hg19: chr12-57422645;