rs144878400

Variant names:

• chr9-114424369-T-A
• rs144878400
• NM_015404.4:c.1381A>T

Your query was ambiguous. Multiple possible variants found:

• chr9-114424369-T-A
• chr9-114424369-T-C
• chr9-114424369-T-G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_015404.4(WHRN):​c.1381A>T​(p.Met461Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000274 in 1,460,072 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M461V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: WHRN NM_015404.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.65
• 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.27015796).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WHRN	NM_015404.4	c.1381A>T	p.Met461Leu	missense_variant	Exon 6 of 12	ENST00000362057.4	NP_056219.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WHRN	ENST00000362057.4	c.1381A>T	p.Met461Leu	missense_variant	Exon 6 of 12	1	NM_015404.4	ENSP00000354623.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1460072 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 726340

African (AFR) AF: 0.00 AC: 0 AN: 33418

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86176

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4276

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1111984

Other (OTH) AF: 0.00 AC: 0 AN: 60238

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	21
DANN	Benign	0.96
DEOGEN2	Benign	0.14	.;.;T
Eigen	Benign	-0.036
Eigen_PC	Benign	0.10
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.80	T;T;T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.27	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.5	.;.;M
PhyloP100		5.6
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-1.2	N;N;N
REVEL	Benign	0.11
Sift	Benign	0.038	D;D;T
Sift4G	Uncertain	0.041	D;D;T
Polyphen		0.0040, 0.012	.;B;B
Vest4		0.55
MutPred		0.54		.;.;Gain of ubiquitination at K465 (P = 0.1111);
MVP		0.22
MPC		0.13
ClinPred		0.88	D
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.53
gMVP		0.38
Mutation Taster		=92/8	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: rs144878400; hg19: chr9-117186649;