rs727503323

Positions:

• chr12-57047998-T-C
• chr12-57047998-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_005379.4(MYO1A):​c.221A>G​(p.Lys74Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K74T) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MYO1A NM_005379.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.390

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.38762158).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYO1A	NM_005379.4	c.221A>G	p.Lys74Arg	missense_variant	3/28	ENST00000300119.8
MYO1A	NM_001256041.2	c.221A>G	p.Lys74Arg	missense_variant	4/29
MYO1A	XM_047428876.1	c.221A>G	p.Lys74Arg	missense_variant	4/29
MYO1A	XM_011538373.3	c.221A>G	p.Lys74Arg	missense_variant	3/25

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYO1A	ENST00000300119.8	c.221A>G	p.Lys74Arg	missense_variant	3/28	1	NM_005379.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251214 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135758

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.31	T;T;.
Eigen	Benign	-0.026
Eigen_PC	Benign	-0.024
FATHMM_MKL	Benign	0.26	N
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.39	T;T;T
MetaSVM	Benign	-0.56	T
MutationAssessor	Benign	1.7	L;L;.
MutationTaster	Benign	0.62	D;D
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-1.2	N;N;N
REVEL	Benign	0.20
Sift	Benign	0.071	T;T;D
Sift4G	Uncertain	0.033	D;D;.
Polyphen		0.82	P;P;.
Vest4		0.47
MutPred		0.57		Loss of methylation at K74 (P = 0.0183);Loss of methylation at K74 (P = 0.0183);Loss of methylation at K74 (P = 0.0183);
MVP		0.78
MPC		0.074
ClinPred		0.48	T
GERP RS		4.5
Varity_R		0.16
gMVP		0.52

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs727503323; hg19: chr12-57441782;