9-114478771-C-T

Variant names:

• chr9-114478771-C-T
• rs111033469
• NM_015404.4:c.619G>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_015404.4(WHRN):​c.619G>A​(p.Ala207Thr) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000000686 in 1,458,160 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A207S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: WHRN NM_015404.4 missense, splice_region
• Scores: Splicing: ADA: 0.9970
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.74
• Publications: 0 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: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WHRN	NM_015404.4	c.619G>A	p.Ala207Thr	missense_variant, splice_region_variant	Exon 2 of 12	ENST00000362057.4	NP_056219.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WHRN	ENST00000362057.4	c.619G>A	p.Ala207Thr	missense_variant, splice_region_variant	Exon 2 of 12	1	NM_015404.4	ENSP00000354623.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1458160 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 725344

African (AFR) AF: 0.00 AC: 0 AN: 33472

American (AMR) AF: 0.00 AC: 0 AN: 44498

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26086

East Asian (EAS) AF: 0.00 AC: 0 AN: 39678

South Asian (SAS) AF: 0.00 AC: 0 AN: 85902

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50942

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111484

Other (OTH) AF: 0.00 AC: 0 AN: 60332

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.49
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.048	T;.
Eigen	Benign	0.16
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.86	D;D
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.36	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.51	N;N
PhyloP100		5.7
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-0.25	N;N
REVEL	Benign	0.15
Sift	Benign	0.24	T;T
Sift4G	Benign	0.19	T;T
Polyphen		0.43	B;P
Vest4		0.41
MutPred		0.79		Loss of MoRF binding (P = 0.1493);Loss of MoRF binding (P = 0.1493);
MVP		0.41
MPC		0.72
ClinPred		0.65	D
GERP RS		5.7
PromoterAI		-0.019	Neutral
Varity_R		0.20
gMVP		0.34
Mutation Taster		=38/62	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.88
SpliceAI score (max)		0.010		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: rs111033469; hg19: chr9-117241051;