8-125024440-T-G

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_StrongBS1_Supporting

The NM_014846.4(WASHC5):c.*177A>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000191 in 649,188 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00023 ( 3 hom. )

Consequence

WASHC5
NM_014846.4 3_prime_UTR

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.603

Variant links:

Genes affected

WASHC5 (HGNC:28984): (WASH complex subunit 5) This gene encodes a 134 kDa protein named strumpellin that is predicted to have multiple transmembrane domains and a spectrin-repeat-containing domain. This ubiquitously expressed gene has its highest expression in skeletal muscle. The protein is named for Strumpell disease; a form of hereditary spastic paraplegia (HSP). Spastic paraplegias are a diverse group of disorders in which the autosomal dominant forms are characterized by progressive, lower extremity spasticity caused by axonal degeneration in the terminal portions of the longest descending and ascending corticospinal tracts. More than 30 loci (SPG1-33) have been implicated in hereditary spastic paraplegia diseases. [provided by RefSeq, Aug 2009]

WASHC5 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.82).

BS1

Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.000233 (116/496846) while in subpopulation MID AF= 0.00445 (10/2246). AF 95% confidence interval is 0.00241. There are 3 homozygotes in gnomad4_exome. There are 81 alleles in male gnomad4_exome subpopulation. Median coverage is 4. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	#exon/exons	MANE
WASHC5	NM_014846.4 linkuse as main transcript	c.*177A>C	3_prime_UTR_variant	29/29	ENST00000318410.12
WASHC5	NM_001330609.2 linkuse as main transcript	c.*177A>C	3_prime_UTR_variant	28/28
WASHC5	XM_047422502.1 linkuse as main transcript	c.*177A>C	3_prime_UTR_variant	30/30

Ensembl

Gene	Transcript	HGVSc	Effect	#exon/exons	TSL	MANE	Appris
WASHC5	ENST00000318410.12 linkuse as main transcript	c.*177A>C	3_prime_UTR_variant	29/29	1	NM_014846.4	P1
WASHC5	ENST00000517845.5 linkuse as main transcript	c.*177A>C	3_prime_UTR_variant	27/27	2
WASHC5	ENST00000519042.2 linkuse as main transcript	n.796A>C	non_coding_transcript_exon_variant	3/3	2

Frequencies

GnomAD3 genomes

AF:

0.0000526

AC:

AN:

152226

Hom.:

Cov.:

show subpopulations

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:

0.000621

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.000233

AC:

116

AN:

496846

Hom.:

Cov.:

AF XY:

0.000305

AC XY:

AN XY:

265874

show subpopulations

Gnomad4 AFR exome

AF:

0.0000764

Gnomad4 AMR exome

AF:

0.0000433

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00134

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000937

Gnomad4 OTH exome

AF:

0.000329

GnomAD4 genome

AF:

0.0000525

AC:

AN:

152342

Hom.:

Cov.:

AF XY:

0.0000268

AC XY:

AN XY:

74490

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000622

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000693

Hom.:

Bravo

AF:

0.0000416

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Hereditary spastic paraplegia 8

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.82

Cadd

Benign

1.9

Dann

Benign

0.57

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over