9-114504788-A-T

Variant names:

• chr9-114504788-A-T
• rs1554747807
• NM_015404.4:c.14T>A

Variant summary

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

The NM_015404.4(WHRN):​c.14T>A​(p.Leu5Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000206 in 1,457,100 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 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. L5P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 34)
  • Exomes 𝑓: 0.0000015 (0 hom.)
• Consequence: WHRN NM_015404.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.29
• 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=0.38357067).

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.14T>A	p.Leu5Gln	missense	Exon 1 of 12	NP_056219.3
	WHRN	NM_001173425.2		c.14T>A	p.Leu5Gln	missense	Exon 1 of 12	NP_001166896.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WHRN	ENST00000362057.4	TSL:1 MANE Select	c.14T>A	p.Leu5Gln	missense	Exon 1 of 12	ENSP00000354623.3
	WHRN	ENST00000674036.9		c.14T>A	p.Leu5Gln	missense	Exon 1 of 11	ENSP00000501297.5
	WHRN	ENST00000699486.2		c.14T>A	p.Leu5Gln	missense	Exon 1 of 9	ENSP00000514397.2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152194 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000153 AC: 2 AN: 1304906 Hom.: 0 Cov.: 34 AF XY: 0.00000156 AC XY: 1 AN XY: 641856

African (AFR) AF: 0.00 AC: 0 AN: 25796

American (AMR) AF: 0.00 AC: 0 AN: 20428

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20600

East Asian (EAS) AF: 0.00 AC: 0 AN: 30916

South Asian (SAS) AF: 0.00 AC: 0 AN: 66688

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 32380

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3802

European-Non Finnish (NFE) AF: 0.00000190 AC: 2 AN: 1050054

Other (OTH) AF: 0.00 AC: 0 AN: 54242

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152194 Hom.: 0 Cov.: 34 AF XY: 0.0000134 AC XY: 1 AN XY: 74362

African (AFR) AF: 0.00 AC: 0 AN: 41454

American (AMR) AF: 0.00 AC: 0 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68022

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.037	T
BayesDel_noAF	Benign	-0.29
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Benign	0.12	T
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.56	T
M_CAP	Pathogenic	0.29	D
MetaRNN	Benign	0.38	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	1.8	L
PhyloP100		5.3
PrimateAI	Pathogenic	0.89	D
PROVEAN	Benign	-0.59	N
REVEL	Benign	0.18
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.98	D
Vest4		0.43
MutPred		0.077		Gain of solvent accessibility (P = 0.0789)
MVP		0.58
MPC		1.6
ClinPred		0.98	D
GERP RS		4.6
Varity_R		0.34
gMVP		0.67
Mutation Taster		=81/19	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs1554747807; hg19: chr9-117267068;