12-57028944-A-T

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 0 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]

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]

TAC3 Gene-Disease associations (from GenCC):

• hypogonadotropic hypogonadism 10 with or without anosmia

  Inheritance: AR Classification: STRONG Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• hypogonadotropic hypogonadism

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYO1A	NM_005379.4	MANE Select	c.3006-63T>A		intron	N/A	NP_005370.1	Q9UBC5
	MYO1A	NM_001256041.2		c.3006-63T>A		intron	N/A	NP_001242970.1	Q9UBC5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYO1A	ENST00000300119.8	TSL:1 MANE Select	c.3006-63T>A		intron	N/A	ENSP00000300119.3	Q9UBC5
	MYO1A	ENST00000442789.6	TSL:1	c.3006-63T>A		intron	N/A	ENSP00000393392.2	Q9UBC5
	MYO1A	ENST00000907120.1		c.3138-63T>A		intron	N/A	ENSP00000577179.1

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

African (AFR) AF: 0.110 AC: 3641 AN: 33142

American (AMR) AF: 0.0193 AC: 837 AN: 43472

Ashkenazi Jewish (ASJ) AF: 0.0700 AC: 1800 AN: 25718

East Asian (EAS) AF: 0.0000761 AC: 3 AN: 39422

South Asian (SAS) AF: 0.0116 AC: 995 AN: 85446

European-Finnish (FIN) AF: 0.0397 AC: 2102 AN: 52972

Middle Eastern (MID) AF: 0.0401 AC: 208 AN: 5192

European-Non Finnish (NFE) AF: 0.0268 AC: 29633 AN: 1104100

Other (OTH) AF: 0.0314 AC: 1879 AN: 59802

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

African (AFR) AF: 0.104 AC: 4275 AN: 41292

American (AMR) AF: 0.0277 AC: 422 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.0745 AC: 258 AN: 3464

East Asian (EAS) AF: 0.000973 AC: 5 AN: 5140

South Asian (SAS) AF: 0.0105 AC: 50 AN: 4774

European-Finnish (FIN) AF: 0.0348 AC: 367 AN: 10546

Middle Eastern (MID) AF: 0.0272 AC: 8 AN: 294

European-Non Finnish (NFE) AF: 0.0291 AC: 1971 AN: 67844

Other (OTH) AF: 0.0451 AC: 95 AN: 2108

Alfa AF: 0.0432 Hom.: 22

Bravo AF: 0.0513

Asia WGS AF: 0.0140 AC: 50 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	1.1
DANN	Benign	0.73
PhyloP100		-0.41
PromoterAI		-0.024	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs56347319; hg19: chr12-57422728;