rs760261757

Positions:

• chr9-114504767-G-A
• chr9-114504767-G-C
• chr9-114504767-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_015404.4(WHRN):​c.35C>T​(p.Ser12Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000245 in 1,347,386 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 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. S12W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.000024 (0 hom.)
• Consequence: WHRN NM_015404.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 3.69

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.34962478).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WHRN	NM_015404.4	c.35C>T	p.Ser12Leu	missense_variant	1/12	ENST00000362057.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WHRN	ENST00000362057.4	c.35C>T	p.Ser12Leu	missense_variant	1/12	1	NM_015404.4	P1
WHRN	ENST00000374057.3	c.35C>T	p.Ser12Leu	missense_variant	1/2	2
WHRN	ENST00000673697.1	c.35C>T	p.Ser12Leu	missense_variant	2/2

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD3 exomes AF: 0.0000324 AC: 3 AN: 92478 Hom.: 0 AF XY: 0.0000192 AC XY: 1 AN XY: 52084

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000579

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: 0.0000268

Gnomad OTH exome AF: 0.000347

GnomAD4 exome AF: 0.0000245 AC: 33 AN: 1347386 Hom.: 0 Cov.: 34 AF XY: 0.0000301 AC XY: 20 AN XY: 664450

Gnomad4 AFR exome AF: 0.0000361

Gnomad4 AMR exome AF: 0.0000682

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000305

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000253

Gnomad4 OTH exome AF: 0.0000357

GnomAD4 genome Cov.: 34

Bravo AF: 0.0000264

ExAC AF: 0.0000246 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Aug 08, 2022	This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 12 of the WHRN protein (p.Ser12Leu). This variant is present in population databases (rs760261757, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with WHRN-related conditions. ClinVar contains an entry for this variant (Variation ID: 228564). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Sep 06, 2016	The S12L variant in the DFNB31 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. Sufficient data from control individuals in the NHLBI Exome Sequencing Project data set were not available to assess whether the S12L variant may be a common benign variant in the general population. The S12L variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved in mammals. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, we interpret S12L as a variant of uncertain significance. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jul 06, 2015

The p.Ser12Leu variant in DFNB31 has not been previously reported in individuals with hearing loss or Usher syndrome. Data from large population studies is insu fficient to assess the frequency of this variant. Computational prediction tools and conservation analysis do not provide strong support for or against an impac t to the protein. In summary, the clinical significance of the p.Ser12Leu varian t is uncertain. -

Usher syndrome type 2D;C1846839:Autosomal recessive nonsyndromic hearing loss 31 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Feb 16, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.38
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.36
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Benign	0.17	T;.
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.70	T;T
M_CAP	Pathogenic	0.60	D
MetaRNN	Benign	0.35	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.6	L;L
MutationTaster	Benign	0.99	D;D
PrimateAI	Pathogenic	0.94	D
PROVEAN	Benign	-1.6	N;N
REVEL	Benign	0.15
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		0.84	P;D
Vest4		0.34
MutPred		0.18		Gain of sheet (P = 0.0085);Gain of sheet (P = 0.0085);
MVP		0.49
MPC		1.4
ClinPred		0.40	T
GERP RS		5.0
Varity_R		0.33
gMVP		0.36

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs760261757; hg19: chr9-117267047;