rs41297175

chr9-114504393-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_015404.4(WHRN):c.409G>C(p.Glu137Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000383 in 1,605,834 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00024 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00040 (7 hom.)
• Consequence: WHRN NM_015404.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 5.45

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0077239275).
• BP6: Variant 9-114504393-C-G is Benign according to our data. Variant chr9-114504393-C-G is described in ClinVar as [Benign]. Clinvar id is 179995.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-114504393-C-G is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000243 (37/152384) while in subpopulation SAS AF= 0.00455 (22/4832). AF 95% confidence interval is 0.00308. There are 0 homozygotes in gnomad4. There are 17 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WHRN	NM_015404.4	c.409G>C	p.Glu137Gln	missense_variant	1/12	ENST00000362057.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WHRN	ENST00000362057.4	c.409G>C	p.Glu137Gln	missense_variant	1/12	1	NM_015404.4	P1
WHRN	ENST00000699486.1	c.133G>C	p.Glu45Gln	missense_variant	1/9
WHRN	ENST00000374057.3	c.409G>C	p.Glu137Gln	missense_variant	1/2	2
WHRN	ENST00000673811.1	n.157G>C		non_coding_transcript_exon_variant	1/7

Frequencies

GnomAD3 genomes AF: 0.000250 AC: 38 AN: 152266 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00476

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000700 AC: 167 AN: 238428 Hom.: 2 AF XY: 0.000910 AC XY: 119 AN XY: 130732

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: 0.00498

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000110

Gnomad OTH exome AF: 0.000505

GnomAD4 exome AF: 0.000398 AC: 578 AN: 1453450 Hom.: 7 Cov.: 32 AF XY: 0.000574 AC XY: 415 AN XY: 723468

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: 0.00545

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000675

Gnomad4 OTH exome AF: 0.000398

GnomAD4 genome AF: 0.000243 AC: 37 AN: 152384 Hom.: 0 Cov.: 33 AF XY: 0.000228 AC XY: 17 AN XY: 74524

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000653

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00455

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000191

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000205 Hom.: 0

Bravo AF: 0.0000831

ExAC AF: 0.000840 AC: 101

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.000178

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Apr 14, 2016

p.Glu137Gln in exon 1 of DFNB31: This variant is not expected to have clinical s ignificance because it has been identified in 0.6% (96/16402) of South Asian chr omosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.o rg; dbSNP rs41297175). -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 26, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.39
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Benign	0.13	T;.
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.76	T;T
M_CAP	Benign	0.0094	T
MetaRNN	Benign	0.0077	T;T
MetaSVM	Benign	-1.2	T
MutationAssessor	Benign	1.9	L;L
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-1.1	N;N
REVEL	Benign	0.15
Sift	Benign	0.051	T;D
Sift4G	Uncertain	0.017	D;D
Polyphen		0.98	D;D
Vest4		0.36
MVP		0.45
MPC		1.4
ClinPred		0.041	T
GERP RS		4.7
Varity_R		0.24
gMVP		0.63

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs41297175; hg19: chr9-117266673;