12-57028944-A-T

Variant names:

• chr12-57028944-A-T
• rs56347319
• NM_005379.4:c.3006-63T>A

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.3006-63T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0303 in 1,600,898 control chromosomes in the GnomAD database, including 1,053 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.049 (276 hom., cov: 31)
  • Exomes 𝑓: 0.028 (777 hom.)
• Consequence: MYO1A NM_005379.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.411

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 (BayesDel_noAF=-0.83).
• BP6: Variant 12-57028944-A-T is Benign according to our data. Variant chr12-57028944-A-T is described in ClinVar as [Benign]. Clinvar id is 1257585.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.101 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYO1A	NM_005379.4	c.3006-63T>A		intron_variant	Intron 27 of 27	ENST00000300119.8	NP_005370.1
MYO1A	NM_001256041.2	c.3006-63T>A		intron_variant	Intron 28 of 28		NP_001242970.1
MYO1A	XM_047428876.1	c.3006-63T>A		intron_variant	Intron 28 of 28		XP_047284832.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYO1A	ENST00000300119.8	c.3006-63T>A		intron_variant	Intron 27 of 27	1	NM_005379.4	ENSP00000300119.3
MYO1A	ENST00000442789.6	c.3006-63T>A		intron_variant	Intron 28 of 28	1		ENSP00000393392.2
MYO1A	ENST00000554234.5	n.*451-63T>A		intron_variant	Intron 23 of 23	5		ENSP00000451033.1
TAC3	ENST00000415231.1	c.-282T>A		upstream_gene_variant		5		ENSP00000402995.1

Frequencies

GnomAD3 genomes AF: 0.0494 AC: 7478 AN: 151514 Hom.: 274 Cov.: 31

Gnomad AFR AF: 0.104

Gnomad AMI AF: 0.0407

Gnomad AMR AF: 0.0277

Gnomad ASJ AF: 0.0745

Gnomad EAS AF: 0.000970

Gnomad SAS AF: 0.0105

Gnomad FIN AF: 0.0348

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0290

Gnomad OTH AF: 0.0455

GnomAD4 exome AF: 0.0284 AC: 41098 AN: 1449266 Hom.: 777 Cov.: 31 AF XY: 0.0280 AC XY: 20124 AN XY: 719574

Gnomad4 AFR exome AF: 0.110

Gnomad4 AMR exome AF: 0.0193

Gnomad4 ASJ exome AF: 0.0700

Gnomad4 EAS exome AF: 0.0000761

Gnomad4 SAS exome AF: 0.0116

Gnomad4 FIN exome AF: 0.0397

Gnomad4 NFE exome AF: 0.0268

Gnomad4 OTH exome AF: 0.0314

GnomAD4 genome AF: 0.0494 AC: 7488 AN: 151632 Hom.: 276 Cov.: 31 AF XY: 0.0480 AC XY: 3555 AN XY: 74100

Gnomad4 AFR AF: 0.104

Gnomad4 AMR AF: 0.0277

Gnomad4 ASJ AF: 0.0745

Gnomad4 EAS AF: 0.000973

Gnomad4 SAS AF: 0.0105

Gnomad4 FIN AF: 0.0348

Gnomad4 NFE AF: 0.0291

Gnomad4 OTH AF: 0.0451

Alfa AF: 0.0432 Hom.: 22

Bravo AF: 0.0513

Asia WGS AF: 0.0140 AC: 50 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jul 05, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	1.1
DANN	Benign	0.73

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: rs56347319; hg19: chr12-57422728;