rs199831544

Positions:

• chr17-18148547-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_016239.4(MYO15A):​c.6743C>T​(p.Ala2248Val) variant causes a missense change. The variant allele was found at a frequency of 0.00133 in 1,552,474 control chromosomes in the GnomAD database, including 31 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00080 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0014 (30 hom.)
• Consequence: MYO15A NM_016239.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 4.54

Genes affected

MYO15A (HGNC:7594): (myosin XVA) This gene encodes an unconventional myosin. This protein differs from other myosins in that it has a long N-terminal extension preceding the conserved motor domain. Studies in mice suggest that this protein is necessary for actin organization in the hair cells of the cochlea. Mutations in this gene have been associated with profound, congenital, neurosensory, nonsyndromal deafness. This gene is located within the Smith-Magenis syndrome region on chromosome 17. Read-through transcripts containing an upstream gene and this gene have been identified, but they are not thought to encode a fusion protein. Several alternatively spliced transcript variants have been described, but their full length sequences have not been determined. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0093669295).
• BP6: Variant 17-18148547-C-T is Benign according to our data. Variant chr17-18148547-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 45755.We mark this variant Likely_benign, oryginal submissions are: {Benign=2, Likely_benign=1, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population sas. gnomad4_exome allele frequency = 0.00139 (1945/1400228) while in subpopulation SAS AF= 0.0182 (1444/79284). AF 95% confidence interval is 0.0174. There are 30 homozygotes in gnomad4_exome. There are 1353 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 30 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYO15A	NM_016239.4	c.6743C>T	p.Ala2248Val	missense_variant	32/66	ENST00000647165.2	NP_057323.3
MYO15A	XM_017024715.3	c.6746C>T	p.Ala2249Val	missense_variant	30/64		XP_016880204.1
MYO15A	XM_017024714.3	c.6683C>T	p.Ala2228Val	missense_variant	29/63		XP_016880203.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYO15A	ENST00000647165.2	c.6743C>T	p.Ala2248Val	missense_variant	32/66		NM_016239.4	ENSP00000495481	P1
MYO15A	ENST00000578999.1	n.277-214C>T		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.000802 AC: 122 AN: 152128 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.0000966

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00662

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0145

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000235

Gnomad OTH AF: 0.000957

GnomAD3 exomes AF: 0.00332 AC: 517 AN: 155910 Hom.: 8 AF XY: 0.00452 AC XY: 373 AN XY: 82552

Gnomad AFR exome AF: 0.000124

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00621

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0191

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000328

Gnomad OTH exome AF: 0.00137

GnomAD4 exome AF: 0.00139 AC: 1945 AN: 1400228 Hom.: 30 Cov.: 32 AF XY: 0.00196 AC XY: 1353 AN XY: 690720

Gnomad4 AFR exome AF: 0.0000632

Gnomad4 AMR exome AF: 0.0000557

Gnomad4 ASJ exome AF: 0.00731

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0182

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000179

Gnomad4 OTH exome AF: 0.00179

GnomAD4 genome AF: 0.000801 AC: 122 AN: 152246 Hom.: 1 Cov.: 32 AF XY: 0.00102 AC XY: 76 AN XY: 74438

Gnomad4 AFR AF: 0.0000963

Gnomad4 AMR AF: 0.000458

Gnomad4 ASJ AF: 0.00662

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0145

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000235

Gnomad4 OTH AF: 0.000947

Alfa AF: 0.000414 Hom.: 1

Bravo AF: 0.000514

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000371 AC: 3

ExAC AF: 0.00242 AC: 236

Asia WGS AF: 0.00520 AC: 19 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 02, 2020	- -

Autosomal recessive nonsyndromic hearing loss 3 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 02, 2015

p.Ala2248Val in exon 32 of MYO15A: This variant is not expected to have clinical significance because it has been identified in 2.2% (171/7918) of South Asian c hromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute .org; dbSNP rs199831544). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.35
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Uncertain	-0.060
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.13	T;D;D
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.88	D;.;D
MetaRNN	Benign	0.0094	T;T;T
MetaSVM	Uncertain	0.52	D
MutationAssessor	Pathogenic	3.2	.;M;M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.56	T
PROVEAN	Uncertain	-3.8	.;D;.
REVEL	Pathogenic	0.66
Sift	Benign	0.043	.;D;.
Sift4G	Uncertain	0.0020	D;D;.
Polyphen		0.91	.;P;P
Vest4		0.38
MVP		0.78
ClinPred		0.095	T
GERP RS		4.3
Varity_R		0.39
gMVP		0.77

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs199831544; hg19: chr17-18051861;