rs121909305

Variant names:

• chr12-57047675-G-A
• rs121909305
• NM_005379.4:c.277C>T

Your query was ambiguous. Multiple possible variants found:

• chr12-57047675-G-A
• chr12-57047675-G-C
• chr12-57047675-G-T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP6 BS2

The NM_005379.4(MYO1A):​c.277C>T​(p.Arg93*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00363 in 1,614,184 control chromosomes in the GnomAD database, including 18 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.0024 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0038 (15 hom.)
• Consequence: MYO1A NM_005379.4 stop_gained
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:9
• Conservation: PhyloP100: 2.55
• Publications: 19 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 -5 ACMG points.

• BP6: Variant 12-57047675-G-A is Benign according to our data. Variant chr12-57047675-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 8146.
• BS2: High AC in GnomAd4 at 366 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.277C>T	p.Arg93*	stop_gained	Exon 4 of 28	NP_005370.1	Q9UBC5
	MYO1A	NM_001256041.2		c.277C>T	p.Arg93*	stop_gained	Exon 5 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.277C>T	p.Arg93*	stop_gained	Exon 4 of 28	ENSP00000300119.3	Q9UBC5
	MYO1A	ENST00000442789.6	TSL:1	c.277C>T	p.Arg93*	stop_gained	Exon 5 of 29	ENSP00000393392.2	Q9UBC5
	MYO1A	ENST00000907120.1		c.277C>T	p.Arg93*	stop_gained	Exon 4 of 28	ENSP00000577179.1

Frequencies

GnomAD3 genomes AF: 0.00240 AC: 366 AN: 152204 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.000820

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00124

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00123

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00429

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.00290 AC: 727 AN: 250558 AF XY: 0.00292

Gnomad AFR exome AF: 0.000617

Gnomad AMR exome AF: 0.00379

Gnomad ASJ exome AF: 0.00110

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00296

Gnomad NFE exome AF: 0.00413

Gnomad OTH exome AF: 0.00491

GnomAD4 exome AF: 0.00376 AC: 5498 AN: 1461862 Hom.: 15 Cov.: 32 AF XY: 0.00366 AC XY: 2660 AN XY: 727230

African (AFR) AF: 0.000777 AC: 26 AN: 33480

American (AMR) AF: 0.00362 AC: 162 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00122 AC: 32 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39696

South Asian (SAS) AF: 0.000568 AC: 49 AN: 86258

European-Finnish (FIN) AF: 0.00307 AC: 164 AN: 53410

Middle Eastern (MID) AF: 0.00104 AC: 6 AN: 5766

European-Non Finnish (NFE) AF: 0.00438 AC: 4875 AN: 1112002

Other (OTH) AF: 0.00303 AC: 183 AN: 60390

GnomAD4 genome AF: 0.00240 AC: 366 AN: 152322 Hom.: 3 Cov.: 32 AF XY: 0.00222 AC XY: 165 AN XY: 74474

African (AFR) AF: 0.000818 AC: 34 AN: 41572

American (AMR) AF: 0.00124 AC: 19 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4830

European-Finnish (FIN) AF: 0.00123 AC: 13 AN: 10610

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

European-Non Finnish (NFE) AF: 0.00429 AC: 292 AN: 68040

Other (OTH) AF: 0.00142 AC: 3 AN: 2114

Alfa AF: 0.00397 Hom.: 10

Bravo AF: 0.00271

TwinsUK AF: 0.00431 AC: 16

ALSPAC AF: 0.00415 AC: 16

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00523 AC: 45

ExAC AF: 0.00320 AC: 389

EpiCase AF: 0.00453

EpiControl AF: 0.00344

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	6	not provided (6)
-	1	1	Autosomal dominant nonsyndromic hearing loss 48 (2)
-	1	1	not specified (2)
-	-	1	MYO1A-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Pathogenic	0.45
CADD	Pathogenic	39
DANN	Uncertain	1.0
Eigen	Uncertain	0.35
Eigen_PC	Benign	0.18
FATHMM_MKL	Uncertain	0.81	D
PhyloP100		2.6
Vest4		0.80
GERP RS		1.9
Mutation Taster		=134/66	disease causing (fs/PTC)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.31		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.31		Position offset: 46

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs121909305; hg19: chr12-57441459; COSMIC: COSV55652631; COSMIC: COSV55652631;