rs145027196

Positions:

• chr12-57036818-A-G

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_005379.4(MYO1A):​c.2228T>C​(p.Ile743Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000663 in 1,614,228 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00041 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000030 (0 hom.)
• Consequence: MYO1A NM_005379.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 4.67

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 Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.020414561).
• BP6: Variant 12-57036818-A-G is Benign according to our data. Variant chr12-57036818-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 164586.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd4 at 63 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYO1A	NM_005379.4	c.2228T>C	p.Ile743Thr	missense_variant	21/28	ENST00000300119.8	NP_005370.1
MYO1A	NM_001256041.2	c.2228T>C	p.Ile743Thr	missense_variant	22/29		NP_001242970.1
MYO1A	XM_047428876.1	c.2228T>C	p.Ile743Thr	missense_variant	22/29		XP_047284832.1
MYO1A	XM_011538373.3	c.2228T>C	p.Ile743Thr	missense_variant	21/25		XP_011536675.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYO1A	ENST00000300119.8	c.2228T>C	p.Ile743Thr	missense_variant	21/28	1	NM_005379.4	ENSP00000300119.3
MYO1A	ENST00000442789.6	c.2228T>C	p.Ile743Thr	missense_variant	22/29	1		ENSP00000393392.2
MYO1A	ENST00000554234.5	n.1742T>C		non_coding_transcript_exon_variant	17/24	5		ENSP00000451033.1

Frequencies

GnomAD3 genomes AF: 0.000414 AC: 63 AN: 152216 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

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: 0.0000147

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000119 AC: 30 AN: 251458 Hom.: 0 AF XY: 0.000118 AC XY: 16 AN XY: 135894

Gnomad AFR exome AF: 0.00166

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000301 AC: 44 AN: 1461894 Hom.: 0 Cov.: 33 AF XY: 0.0000234 AC XY: 17 AN XY: 727248

Gnomad4 AFR exome AF: 0.00105

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.0000993

GnomAD4 genome AF: 0.000414 AC: 63 AN: 152334 Hom.: 0 Cov.: 32 AF XY: 0.000483 AC XY: 36 AN XY: 74490

Gnomad4 AFR AF: 0.00144

Gnomad4 AMR AF: 0.0000653

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000309 Hom.: 0

Bravo AF: 0.000442

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000165 AC: 20

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

May 21, 2016

p.Ile743Thr in exon 21 MYO1A: Recent evidence has disqualified an association between variants in the MYO1A gene and hearing loss, and therefore this variant is likely benign (Eisenberger 2014). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	19
DANN	Benign	0.83
DEOGEN2	Benign	0.042	T;T
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.033
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.64	.;T
M_CAP	Benign	0.072	D
MetaRNN	Benign	0.020	T;T
MetaSVM	Benign	-0.85	T
MutationAssessor	Benign	1.0	L;L
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-0.71	N;N
REVEL	Benign	0.18
Sift	Benign	0.56	T;T
Sift4G	Benign	0.29	T;T
Polyphen		0.18	B;B
Vest4		0.38
MVP		0.77
MPC		0.10
ClinPred		0.043	T
GERP RS		5.4
Varity_R		0.12
gMVP		0.18

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs145027196; hg19: chr12-57430602;