rs149897775

Positions:

• chr9-114403897-G-A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BS1_Supporting

The NM_015404.4(WHRN):​c.2417C>T​(p.Pro806Leu) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0000758 in 1,610,500 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P806Q) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.00036 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000046 (0 hom.)
• Consequence: WHRN NM_015404.4 missense, splice_region
• Scores: Splicing: ADA: 0.6713
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 6.60

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 -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.036877632).
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000361 (55/152254) while in subpopulation AFR AF= 0.00123 (51/41548). AF 95% confidence interval is 0.000958. There are 0 homozygotes in gnomad4. There are 24 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WHRN	NM_015404.4	c.2417C>T	p.Pro806Leu	missense_variant, splice_region_variant	10/12	ENST00000362057.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WHRN	ENST00000362057.4	c.2417C>T	p.Pro806Leu	missense_variant, splice_region_variant	10/12	1	NM_015404.4	P1

Frequencies

GnomAD3 genomes AF: 0.000355 AC: 54 AN: 152136 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00121

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: 0.00316

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000964 AC: 24 AN: 248840 Hom.: 0 AF XY: 0.0000742 AC XY: 10 AN XY: 134714

Gnomad AFR exome AF: 0.00148

Gnomad AMR exome AF: 0.00

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000459 AC: 67 AN: 1458246 Hom.: 0 Cov.: 32 AF XY: 0.0000400 AC XY: 29 AN XY: 725584

Gnomad4 AFR exome AF: 0.00161

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000630

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome AF: 0.000361 AC: 55 AN: 152254 Hom.: 0 Cov.: 33 AF XY: 0.000322 AC XY: 24 AN XY: 74442

Gnomad4 AFR AF: 0.00123

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: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000721 Hom.: 0

Bravo AF: 0.000317

ESP6500AA AF: 0.00159 AC: 7

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000140 AC: 17

EpiCase AF: 0.000164

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 25, 2015	The p.Pro806Leu variant in DFNB31 has not been previously reported in individual s with hearing loss, but has been identified in 0.16% (17/10380) of African chro mosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.or g; dbSNP rs149897775). Computational prediction tools and conservation analyses suggest that the p.Pro806Leu variant may impact the protein, though this informa tion is not predictive enough to determine pathogenicity. In summary, the clinic al significance of this variant is uncertain. -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 11, 2024	Variant summary: WHRN c.2417C>T (p.Pro806Leu) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 9.6e-05 in 248840 control chromosomes, predominantly at a frequency of 0.0015 within the African or African-American subpopulation in the gnomAD database. This frequency is not significantly higher than estimated for a pathogenic variant in WHRN causing Usher Syndrome (9.6e-05 vs 0.0038), allowing no conclusion about variant significance. c.2417C>T has been reported in the literature in an individual affected with non-syndromic hearing loss (Sloan-Heggen_2016). This report does not provide unequivocal conclusions about association of the variant with Usher Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 26969326). ClinVar contains an entry for this variant (Variation ID: 228562). Based on the evidence outlined above, the variant was classified as uncertain significance. -

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	May 05, 2021	Observed in published literature in a patient with hearing loss, described as c.1268 C>T, p.P423L using alternate nomenclature (Sloan-Heggen et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26969326) -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jan 26, 2024	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 806 of the WHRN protein (p.Pro806Leu). This variant is present in population databases (rs149897775, gnomAD 0.1%). This missense change has been observed in individual(s) with early-onset hearing loss (PMID: 26969326). This variant is also known as c.1268C>T (p.Pro423Leu). ClinVar contains an entry for this variant (Variation ID: 228562). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.30
CADD	Pathogenic	33
DANN	Uncertain	1.0
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.90	D;D;D
M_CAP	Benign	0.033	D
MetaRNN	Benign	0.037	T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.52	T
PROVEAN	Uncertain	-2.4	N;N;D
REVEL	Benign	0.16
Sift	Uncertain	0.0020	D;D;D
Sift4G	Uncertain	0.012	D;D;D
Polyphen		0.99, 0.98	.;D;D
Vest4		0.54
MVP		0.50
MPC		0.49
ClinPred		0.17	T
GERP RS		5.0
Varity_R		0.24
gMVP		0.39

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.67
dbscSNV1_RF	Benign	0.51
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: rs149897775; hg19: chr9-117166177;