12-57029252-G-A

Variant names:

• chr12-57029252-G-A
• rs772899759
• NM_005379.4:c.2885C>T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_005379.4(MYO1A):​c.2885C>T​(p.Ser962Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000192 in 1,613,844 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: MYO1A NM_005379.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.94
• Publications: 3 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]

MYO1A Gene-Disease associations (from GenCC):

• nonsyndromic genetic hearing loss

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.20593637).
• BS2: High AC in GnomAd4 at 8 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.2885C>T	p.Ser962Leu	missense	Exon 27 of 28	NP_005370.1	Q9UBC5
	MYO1A	NM_001256041.2		c.2885C>T	p.Ser962Leu	missense	Exon 28 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.2885C>T	p.Ser962Leu	missense	Exon 27 of 28	ENSP00000300119.3	Q9UBC5
	MYO1A	ENST00000442789.6	TSL:1	c.2885C>T	p.Ser962Leu	missense	Exon 28 of 29	ENSP00000393392.2	Q9UBC5
	MYO1A	ENST00000907120.1		c.3017C>T	p.Ser1006Leu	missense	Exon 27 of 28	ENSP00000577179.1

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 152030 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.00000797 AC: 2 AN: 250908 AF XY: 0.00000737

Gnomad AFR exome AF: 0.0000618

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: 0.00000882

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000157 AC: 23 AN: 1461814 Hom.: 0 Cov.: 33 AF XY: 0.0000151 AC XY: 11 AN XY: 727206

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: 26136

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

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53346

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

European-Non Finnish (NFE) AF: 0.0000162 AC: 18 AN: 1112006

Other (OTH) AF: 0.0000497 AC: 3 AN: 60396

GnomAD4 genome AF: 0.0000526 AC: 8 AN: 152030 Hom.: 0 Cov.: 32 AF XY: 0.0000673 AC XY: 5 AN XY: 74260

African (AFR) AF: 0.000121 AC: 5 AN: 41380

American (AMR) AF: 0.00 AC: 0 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10596

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 67992

Other (OTH) AF: 0.000479 AC: 1 AN: 2088

Alfa AF: 0.0000681 Hom.: 0

Bravo AF: 0.0000378

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.090	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Benign	0.056	T
Eigen	Benign	-0.50
Eigen_PC	Benign	-0.49
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.63	T
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.21	T
MetaSVM	Benign	-0.58	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		5.9
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-1.6	N
REVEL	Uncertain	0.32
Sift	Benign	0.20	T
Sift4G	Benign	0.38	T
Polyphen		0.33	B
Vest4		0.12
MutPred		0.54		Loss of disorder (P = 0.0118)
MVP		0.72
MPC		0.074
ClinPred		0.24	T
GERP RS		3.3
PromoterAI		0.040	Neutral
Varity_R		0.047
gMVP		0.11
Mutation Taster		=87/13	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs772899759; hg19: chr12-57423036; COSMIC: COSV55654779; COSMIC: COSV55654779;