9-114406753-A-T

Position:

• chr9-114406753-A-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_015404.4(WHRN):​c.1838T>A​(p.Met613Lys) 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. 15/21 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. M613T) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: WHRN NM_015404.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.24

Genes affected

WHRN (HGNC:16361): (whirlin) This gene is thought to function in the organization and stabilization of sterocilia elongation and actin cystoskeletal assembly, based on studies of the related mouse gene. Mutations in this gene have been associated with autosomal recessive non-syndromic deafness and Usher Syndrome. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Nov 2016]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.026768655).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
WHRN	NM_015404.4	c.1838T>A	p.Met613Lys	missense_variant	9/12	ENST00000362057.4	NP_056219.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
WHRN	ENST00000362057.4	c.1838T>A	p.Met613Lys	missense_variant	9/12	1	NM_015404.4	ENSP00000354623	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 99

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.73
CADD	Benign	3.8
DANN	Benign	0.48
DEOGEN2	Benign	0.050	.;.;T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.0082	N
LIST_S2	Benign	0.30	T;T;T
M_CAP	Benign	0.0022	T
MetaRNN	Benign	0.027	T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.0	.;.;N
MutationTaster	Benign	1.0	P;P;P
PrimateAI	Benign	0.28	T
PROVEAN	Benign	0.88	N;N;N
REVEL	Benign	0.054
Sift	Benign	0.45	T;T;T
Sift4G	Benign	0.90	T;T;T
Polyphen		0.0	.;B;B
Vest4		0.079
MutPred		0.30		.;.;Gain of ubiquitination at M613 (P = 0.0037);
MVP		0.040
MPC		0.19
ClinPred		0.067	T
GERP RS		0.056
Varity_R		0.11
gMVP		0.26

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

Publications

LitVar

Other links and lift over

dbSNP: rs942519; hg19: chr9-117169033;