rs370178817

chr9-114424390-C-Gchr9-114424390-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_015404.4(WHRN):c.1360G>C(p.Val454Leu) 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. 13/20 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. V454I) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: WHRN NM_015404.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.216

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15015921).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WHRN	NM_015404.4	c.1360G>C	p.Val454Leu	missense_variant	6/12	ENST00000362057.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WHRN	ENST00000362057.4	c.1360G>C	p.Val454Leu	missense_variant	6/12	1	NM_015404.4	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.61
Cadd	Benign	0.44
Dann	Benign	0.96
Eigen	Benign	-0.51
Eigen_PC	Benign	-0.43
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Uncertain	0.87	D;D;D
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.15	T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	0.54	D;N;N
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.55	N;N;N
REVEL	Benign	0.032
Sift	Benign	0.049	D;D;T
Sift4G	Uncertain	0.020	D;D;D
Polyphen		0.36, 0.13	.;B;B
Vest4		0.21
MutPred		0.62		.;.;Gain of relative solvent accessibility (P = 0.0249);
MVP		0.17
MPC		0.13
ClinPred		0.44	T
GERP RS		0.53
Varity_R		0.032
gMVP		0.32

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: rs370178817; hg19: chr9-117186670;