rs199831544

Variant names:

• chr17-18148547-C-T
• rs199831544
• NM_016239.4:c.6743C>T

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 4 publications found

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]

MYO15A Gene-Disease associations (from GenCC):

• autosomal recessive nonsyndromic hearing loss 3

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), PanelApp Australia
• nonsyndromic genetic hearing loss

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 45755.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000801 (122/152246) while in subpopulation SAS AF = 0.0145 (70/4828). AF 95% confidence interval is 0.0118. There are 1 homozygotes in GnomAd4. There are 76 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 30 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016239.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYO15A	NM_016239.4	MANE Select	c.6743C>T	p.Ala2248Val	missense	Exon 32 of 66	NP_057323.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYO15A	ENST00000647165.2	MANE Select	c.6743C>T	p.Ala2248Val	missense	Exon 32 of 66	ENSP00000495481.1
	MYO15A	ENST00000578999.1	TSL:5	n.277-214C>T		intron	N/A

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

GnomAD2 exomes AF: 0.00332 AC: 517 AN: 155910 AF XY: 0.00452

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 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

African (AFR) AF: 0.0000632 AC: 2 AN: 31628

American (AMR) AF: 0.0000557 AC: 2 AN: 35914

Ashkenazi Jewish (ASJ) AF: 0.00731 AC: 184 AN: 25188

East Asian (EAS) AF: 0.00 AC: 0 AN: 35786

South Asian (SAS) AF: 0.0182 AC: 1444 AN: 79284

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49272

Middle Eastern (MID) AF: 0.00281 AC: 16 AN: 5698

European-Non Finnish (NFE) AF: 0.000179 AC: 193 AN: 1079408

Other (OTH) AF: 0.00179 AC: 104 AN: 58050

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

African (AFR) AF: 0.0000963 AC: 4 AN: 41550

American (AMR) AF: 0.000458 AC: 7 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00662 AC: 23 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.0145 AC: 70 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

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

European-Non Finnish (NFE) AF: 0.000235 AC: 16 AN: 67992

Other (OTH) AF: 0.000947 AC: 2 AN: 2112

Alfa AF: 0.000674 Hom.: 2

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

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	1	-	Autosomal recessive nonsyndromic hearing loss 3 (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.88	D
MetaRNN	Benign	0.0094	T
MetaSVM	Uncertain	0.52	D
MutationAssessor	Pathogenic	3.2	M
PhyloP100		4.5
PrimateAI	Uncertain	0.56	T
PROVEAN	Uncertain	-3.8	D
REVEL	Pathogenic	0.66
Sift	Benign	0.043	D
Sift4G	Uncertain	0.0020	D
Polyphen		0.91	P
Vest4		0.38
MVP		0.78
ClinPred		0.095	T
GERP RS		4.3
Varity_R		0.39
gMVP		0.77
Mutation Taster		=46/54	disease causing

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

Other links and lift over

dbSNP: rs199831544; hg19: chr17-18051861;