12-57028792-T-G

Position:

• chr12-57028792-T-G

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.3095A>C​(p.Lys1032Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00083 in 1,614,070 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0045 (7 hom., cov: 31)
  • Exomes 𝑓: 0.00045 (9 hom.)
• Consequence: MYO1A NM_005379.4 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 3.20

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.01078254).
• BP6: Variant 12-57028792-T-G is Benign according to our data. Variant chr12-57028792-T-G is described in ClinVar as [Likely_benign]. Clinvar id is 309895.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 682 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYO1A	NM_005379.4	c.3095A>C	p.Lys1032Thr	missense_variant	28/28	ENST00000300119.8	NP_005370.1
MYO1A	NM_001256041.2	c.3095A>C	p.Lys1032Thr	missense_variant	29/29		NP_001242970.1
MYO1A	XM_047428876.1	c.3095A>C	p.Lys1032Thr	missense_variant	29/29		XP_047284832.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYO1A	ENST00000300119.8	c.3095A>C	p.Lys1032Thr	missense_variant	28/28	1	NM_005379.4	ENSP00000300119	P1
MYO1A	ENST00000442789.6	c.3095A>C	p.Lys1032Thr	missense_variant	29/29	1		ENSP00000393392	P1
TAC3	ENST00000415231.1	c.-130A>C		5_prime_UTR_variant	1/7	5		ENSP00000402995	P1
MYO1A	ENST00000554234.5	c.*540A>C		3_prime_UTR_variant, NMD_transcript_variant	24/24	5		ENSP00000451033

Frequencies

GnomAD3 genomes AF: 0.00448 AC: 682 AN: 152070 Hom.: 7 Cov.: 31

Gnomad AFR AF: 0.0158

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00124

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00119 AC: 297 AN: 250124 Hom.: 3 AF XY: 0.000820 AC XY: 111 AN XY: 135330

Gnomad AFR exome AF: 0.0163

Gnomad AMR exome AF: 0.000694

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: 0.00000889

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.000449 AC: 657 AN: 1461882 Hom.: 9 Cov.: 31 AF XY: 0.000395 AC XY: 287 AN XY: 727244

Gnomad4 AFR exome AF: 0.0160

Gnomad4 AMR exome AF: 0.000760

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000189

Gnomad4 OTH exome AF: 0.000993

GnomAD4 genome AF: 0.00448 AC: 682 AN: 152188 Hom.: 7 Cov.: 31 AF XY: 0.00448 AC XY: 333 AN XY: 74398

Gnomad4 AFR AF: 0.0158

Gnomad4 AMR AF: 0.00124

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.000824 Hom.: 0

Bravo AF: 0.00524

ESP6500AA AF: 0.0168 AC: 74

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00143 AC: 173

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 19, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.38
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.36
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.11	T;T
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.79	.;T
MetaRNN	Benign	0.011	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.8	M;M
MutationTaster	Benign	0.82	D;D;D;D
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-2.2	N;N
REVEL	Benign	0.24
Sift	Uncertain	0.0050	D;D
Sift4G	Uncertain	0.054	T;T
Polyphen		1.0	D;D
Vest4		0.45
MVP		0.68
MPC		0.41
ClinPred		0.031	T
GERP RS		4.2
Varity_R		0.21
gMVP		0.60

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: rs77915386; hg19: chr12-57422576;