9-114424385-A-G

Variant names:

• chr9-114424385-A-G
• rs111033459
• NM_015404.4:c.1365T>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_015404.4(WHRN):​c.1365T>C​(p.Ser455Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00376 in 1,612,580 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. S455S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0028 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0039 (13 hom.)
• Consequence: WHRN NM_015404.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:6
• Conservation: PhyloP100: -5.16
• Publications: 3 publications found

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]

WHRN Gene-Disease associations (from GenCC):

• Usher syndrome type 2D

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), PanelApp Australia, Ambry Genetics, G2P
• autosomal recessive nonsyndromic hearing loss 31

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, PanelApp Australia
• nonsyndromic genetic hearing loss

  Inheritance: AR Classification: MODERATE Submitted by: ClinGen
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Usher syndrome type 2

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 9-114424385-A-G is Benign according to our data. Variant chr9-114424385-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 45652.
• BP7: Synonymous conserved (PhyloP=-5.16 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00285 (434/152288) while in subpopulation NFE AF = 0.00454 (309/68004). AF 95% confidence interval is 0.00413. There are 2 homozygotes in GnomAd4. There are 194 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015404.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WHRN	NM_015404.4	MANE Select	c.1365T>C	p.Ser455Ser	synonymous	Exon 6 of 12	NP_056219.3
	WHRN	NM_001173425.2		c.1365T>C	p.Ser455Ser	synonymous	Exon 6 of 12	NP_001166896.1
	WHRN	NM_001346890.1		c.312T>C	p.Ser104Ser	synonymous	Exon 2 of 8	NP_001333819.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WHRN	ENST00000362057.4	TSL:1 MANE Select	c.1365T>C	p.Ser455Ser	synonymous	Exon 6 of 12	ENSP00000354623.3
	WHRN	ENST00000265134.10	TSL:1	c.216T>C	p.Ser72Ser	synonymous	Exon 6 of 12	ENSP00000265134.6
	WHRN	ENST00000866780.1		c.1365T>C	p.Ser455Ser	synonymous	Exon 6 of 12	ENSP00000536839.1

Frequencies

GnomAD3 genomes AF: 0.00285 AC: 433 AN: 152170 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000965

Gnomad AMI AF: 0.0164

Gnomad AMR AF: 0.00144

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00329

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00456

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00247 AC: 621 AN: 251384 AF XY: 0.00232

Gnomad AFR exome AF: 0.000738

Gnomad AMR exome AF: 0.000347

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00323

Gnomad NFE exome AF: 0.00432

Gnomad OTH exome AF: 0.00261

GnomAD4 exome AF: 0.00385 AC: 5624 AN: 1460292 Hom.: 13 Cov.: 34 AF XY: 0.00372 AC XY: 2699 AN XY: 726450

African (AFR) AF: 0.000419 AC: 14 AN: 33430

American (AMR) AF: 0.000492 AC: 22 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.000859 AC: 74 AN: 86182

European-Finnish (FIN) AF: 0.00367 AC: 196 AN: 53420

Middle Eastern (MID) AF: 0.000893 AC: 4 AN: 4478

European-Non Finnish (NFE) AF: 0.00463 AC: 5153 AN: 1111976

Other (OTH) AF: 0.00267 AC: 161 AN: 60254

GnomAD4 genome AF: 0.00285 AC: 434 AN: 152288 Hom.: 2 Cov.: 32 AF XY: 0.00261 AC XY: 194 AN XY: 74470

African (AFR) AF: 0.000962 AC: 40 AN: 41562

American (AMR) AF: 0.00144 AC: 22 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00166 AC: 8 AN: 4828

European-Finnish (FIN) AF: 0.00329 AC: 35 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00454 AC: 309 AN: 68004

Other (OTH) AF: 0.00237 AC: 5 AN: 2114

Alfa AF: 0.00359 Hom.: 0

Bravo AF: 0.00265

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00442

EpiControl AF: 0.00379

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	4	not provided (5)
-	-	2	not specified (2)
-	1	-	Autosomal recessive nonsyndromic hearing loss 31 (1)
-	1	-	Usher syndrome type 2D (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.084
DANN	Benign	0.44
PhyloP100		-5.2
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs111033459; hg19: chr9-117186665;