chr9-114504758-G-A

Position:

• chr9-114504758-G-A

Variant summary

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

The NM_015404.4(WHRN):​c.44C>T​(p.Thr15Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000163 in 1,353,568 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 (★★).

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: WHRN NM_015404.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 1.79

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=0.09767106).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WHRN	NM_015404.4	c.44C>T	p.Thr15Ile	missense_variant	1/12	ENST00000362057.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WHRN	ENST00000362057.4	c.44C>T	p.Thr15Ile	missense_variant	1/12	1	NM_015404.4	P1
WHRN	ENST00000374057.3	c.44C>T	p.Thr15Ile	missense_variant	1/2	2
WHRN	ENST00000673697.1	c.44C>T	p.Thr15Ile	missense_variant	2/2

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD3 exomes AF: 0.0000294 AC: 3 AN: 102036 Hom.: 0 AF XY: 0.0000525 AC XY: 3 AN XY: 57156

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000169

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000163 AC: 22 AN: 1353568 Hom.: 0 Cov.: 34 AF XY: 0.0000270 AC XY: 18 AN XY: 667644

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000214

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000281

Gnomad4 OTH exome AF: 0.0000532

GnomAD4 genome Cov.: 34

Bravo AF: 0.00000378

ExAC AF: 0.0000504 AC: 4

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

May 07, 2013

Variant classified as Uncertain Significance - Favor Benign. The Thr15Ile varian t in DFNB31 has not been reported in the literature nor previously identified by our laboratory. Computational analyses (biochemical amino acid properties, cons ervation, AlignGVGD, PolyPhen2, and SIFT) do not provide strong support for or a gainst an impact to the protein. In summary, additional data is needed to determ ine the clinical significance of this variant. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Nov 17, 2021

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: "Deleterious"; PolyPhen-2: "Probably 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. ClinVar contains an entry for this variant (Variation ID: 163057). This variant has not been reported in the literature in individuals affected with WHRN-related conditions. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 15 of the WHRN protein (p.Thr15Ile). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.33
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.46
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.13	T;.
Eigen	Benign	0.070
Eigen_PC	Benign	0.16
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.54	T;T
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.098	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.69	N;N
MutationTaster	Benign	0.89	N;N
PrimateAI	Pathogenic	0.94	D
PROVEAN	Benign	-1.4	N;N
REVEL	Benign	0.095
Sift	Pathogenic	0.0	D;D
Sift4G	Benign	0.069	T;D
Polyphen		0.62	P;P
Vest4		0.14
MutPred		0.12		Loss of glycosylation at T15 (P = 0.0224);Loss of glycosylation at T15 (P = 0.0224);
MVP		0.32
MPC		1.6
ClinPred		0.30	T
GERP RS		4.1
Varity_R		0.099
gMVP		0.42

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: rs727502957; hg19: chr9-117267038;