12-57028759-T-C

Variant names:

• chr12-57028759-T-C
• rs370617353
• NM_005379.4:c.3128A>G

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_005379.4(MYO1A):​c.3128A>G​(p.Gln1043Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000836 in 1,614,058 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000066 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000086 (1 hom.)
• Consequence: MYO1A NM_005379.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -0.228
• Publications: 1 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: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P, PanelApp Australia
• hypogonadotropic hypogonadism

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.007772088).
• BP6: Variant 12-57028759-T-C is Benign according to our data. Variant chr12-57028759-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 227659.
• BS2: High AC in GnomAd4 at 10 AD gene.

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.3128A>G	p.Gln1043Arg	missense	Exon 28 of 28	NP_005370.1	Q9UBC5
	MYO1A	NM_001256041.2		c.3128A>G	p.Gln1043Arg	missense	Exon 29 of 29	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.3128A>G	p.Gln1043Arg	missense	Exon 28 of 28	ENSP00000300119.3	Q9UBC5
	MYO1A	ENST00000442789.6	TSL:1	c.3128A>G	p.Gln1043Arg	missense	Exon 29 of 29	ENSP00000393392.2	Q9UBC5
	MYO1A	ENST00000907120.1		c.3260A>G	p.Gln1087Arg	missense	Exon 28 of 28	ENSP00000577179.1

Frequencies

GnomAD3 genomes AF: 0.0000657 AC: 10 AN: 152126 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00187

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000203 AC: 51 AN: 251010 AF XY: 0.000177

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000654

GnomAD4 exome AF: 0.0000855 AC: 125 AN: 1461814 Hom.: 1 Cov.: 31 AF XY: 0.0000866 AC XY: 63 AN XY: 727216

African (AFR) AF: 0.0000299 AC: 1 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00118 AC: 102 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53408

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111952

Other (OTH) AF: 0.000331 AC: 20 AN: 60392

GnomAD4 genome AF: 0.0000657 AC: 10 AN: 152244 Hom.: 0 Cov.: 31 AF XY: 0.0000806 AC XY: 6 AN XY: 74446

African (AFR) AF: 0.0000241 AC: 1 AN: 41546

American (AMR) AF: 0.00 AC: 0 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00187 AC: 9 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68008

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000227

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.000222 AC: 27

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.094
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	0.40
DANN	Benign	0.62
DEOGEN2	Benign	0.035	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.084	N
LIST_S2	Benign	0.41	T
M_CAP	Benign	0.057	D
MetaRNN	Benign	0.0078	T
MetaSVM	Benign	-0.84	T
MutationAssessor	Benign	0.60	N
PhyloP100		-0.23
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.55	N
REVEL	Benign	0.23
Sift	Benign	0.66	T
Sift4G	Benign	0.18	T
Polyphen		0.0	B
Vest4		0.082
MutPred		0.55		Gain of MoRF binding (P = 0.0064)
MVP		0.38
MPC		0.088
ClinPred		0.017	T
GERP RS		-0.69
PromoterAI		0.011	Neutral
Varity_R		0.025
gMVP		0.29
Mutation Taster		=100/0	polymorphism

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: rs370617353; hg19: chr12-57422543;