rs144384395

Variant names:

• chr12-57036315-T-C
• rs144384395
• NM_005379.4:c.2341A>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.2341A>G​(p.Lys781Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00137 in 1,613,606 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 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 0.0010 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0014 (4 hom.)
• Consequence: MYO1A NM_005379.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 0.680
• Publications: 5 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: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.011663854).
• BP6: Variant 12-57036315-T-C is Benign according to our data. Variant chr12-57036315-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 164583.
• BS2: High AC in GnomAd4 at 153 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.2341A>G	p.Lys781Glu	missense	Exon 22 of 28	NP_005370.1	Q9UBC5
	MYO1A	NM_001256041.2		c.2341A>G	p.Lys781Glu	missense	Exon 23 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.2341A>G	p.Lys781Glu	missense	Exon 22 of 28	ENSP00000300119.3	Q9UBC5
	MYO1A	ENST00000442789.6	TSL:1	c.2341A>G	p.Lys781Glu	missense	Exon 23 of 29	ENSP00000393392.2	Q9UBC5
	MYO1A	ENST00000907120.1		c.2473A>G	p.Lys825Glu	missense	Exon 22 of 28	ENSP00000577179.1

Frequencies

GnomAD3 genomes AF: 0.00101 AC: 153 AN: 152160 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00183

Gnomad ASJ AF: 0.00461

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00147

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.000796 AC: 200 AN: 251146 AF XY: 0.000884

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000983

Gnomad ASJ exome AF: 0.00337

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00107

Gnomad OTH exome AF: 0.000979

GnomAD4 exome AF: 0.00141 AC: 2057 AN: 1461446 Hom.: 4 Cov.: 32 AF XY: 0.00134 AC XY: 976 AN XY: 727030

African (AFR) AF: 0.000179 AC: 6 AN: 33466

American (AMR) AF: 0.00132 AC: 59 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.00383 AC: 100 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.000104 AC: 9 AN: 86238

European-Finnish (FIN) AF: 0.0000374 AC: 2 AN: 53408

Middle Eastern (MID) AF: 0.000696 AC: 4 AN: 5750

European-Non Finnish (NFE) AF: 0.00159 AC: 1765 AN: 1111684

Other (OTH) AF: 0.00186 AC: 112 AN: 60368

GnomAD4 genome AF: 0.00101 AC: 153 AN: 152160 Hom.: 0 Cov.: 32 AF XY: 0.00106 AC XY: 79 AN XY: 74330

African (AFR) AF: 0.0000965 AC: 4 AN: 41430

American (AMR) AF: 0.00183 AC: 28 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.00461 AC: 16 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5200

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.0000943 AC: 1 AN: 10610

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

European-Non Finnish (NFE) AF: 0.00147 AC: 100 AN: 68028

Other (OTH) AF: 0.00191 AC: 4 AN: 2092

Alfa AF: 0.00120 Hom.: 0

Bravo AF: 0.00110

TwinsUK AF: 0.00162 AC: 6

ALSPAC AF: 0.00234 AC: 9

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00233 AC: 20

ExAC AF: 0.000692 AC: 84

EpiCase AF: 0.00153

EpiControl AF: 0.00119

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	3	not specified (4)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	17
DANN	Benign	0.93
DEOGEN2	Benign	0.042	T
Eigen	Benign	-0.68
Eigen_PC	Benign	-0.57
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.52	T
M_CAP	Benign	0.032	D
MetaRNN	Benign	0.012	T
MetaSVM	Benign	-0.78	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		0.68
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.43	N
REVEL	Benign	0.22
Sift	Benign	0.37	T
Sift4G	Benign	0.30	T
Polyphen		0.020	B
Vest4		0.30
MVP		0.68
MPC		0.12
ClinPred		0.013	T
GERP RS		2.2
Varity_R		0.071
gMVP		0.23
Mutation Taster		=94/6	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: rs144384395; hg19: chr12-57430099; COSMIC: COSV99037929; COSMIC: COSV99037929;