8-125024539-T-C

Variant names:

• chr8-125024539-T-C
• rs188863489
• NM_014846.4:c.*78A>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_014846.4(WASHC5):​c.*78A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000316 in 1,131,868 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 Benign (★).

• Frequency:
  • Genomes: 𝑓 0.00039 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00030 (2 hom.)
• Consequence: WASHC5 NM_014846.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.618
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• Ritscher-Schinzel syndrome 1

  Inheritance: AR Classification: STRONG, LIMITED Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp
• hereditary spastic paraplegia 8

  Inheritance: AD Classification: MODERATE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• Ritscher-Schinzel syndrome

  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=-0.83).
• BP6: Variant 8-125024539-T-C is Benign according to our data. Variant chr8-125024539-T-C is described in ClinVar as [Benign]. Clinvar id is 361708.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000394 (60/152330) while in subpopulation AMR AF = 0.00085 (13/15298). AF 95% confidence interval is 0.000502. There are 1 homozygotes in GnomAd4. There are 30 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 2 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WASHC5	NM_014846.4	c.*78A>G		3_prime_UTR_variant	Exon 29 of 29	ENST00000318410.12	NP_055661.3
WASHC5	NM_001330609.2	c.*78A>G		3_prime_UTR_variant	Exon 28 of 28		NP_001317538.1
WASHC5	XM_047422502.1	c.*78A>G		3_prime_UTR_variant	Exon 30 of 30		XP_047278458.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WASHC5	ENST00000318410.12	c.*78A>G		3_prime_UTR_variant	Exon 29 of 29	1	NM_014846.4	ENSP00000318016.7
WASHC5	ENST00000519042.2	n.697A>G		non_coding_transcript_exon_variant	Exon 3 of 3	2
WASHC5	ENST00000517845.5	c.*78A>G		3_prime_UTR_variant	Exon 27 of 27	2		ENSP00000429676.1

Frequencies

GnomAD3 genomes AF: 0.000394 AC: 60 AN: 152212 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000851

Gnomad ASJ AF: 0.00951

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.000956

GnomAD4 exome AF: 0.000304 AC: 298 AN: 979538 Hom.: 2 Cov.: 13 AF XY: 0.000333 AC XY: 169 AN XY: 507468

African (AFR) AF: 0.00 AC: 0 AN: 24216

American (AMR) AF: 0.000162 AC: 7 AN: 43320

Ashkenazi Jewish (ASJ) AF: 0.00925 AC: 211 AN: 22804

East Asian (EAS) AF: 0.00 AC: 0 AN: 37424

South Asian (SAS) AF: 0.00 AC: 0 AN: 75772

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52900

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4830

European-Non Finnish (NFE) AF: 0.0000653 AC: 44 AN: 673890

Other (OTH) AF: 0.000811 AC: 36 AN: 44382

GnomAD4 genome AF: 0.000394 AC: 60 AN: 152330 Hom.: 1 Cov.: 32 AF XY: 0.000403 AC XY: 30 AN XY: 74490

African (AFR) AF: 0.0000241 AC: 1 AN: 41568

American (AMR) AF: 0.000850 AC: 13 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00951 AC: 33 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

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

European-Non Finnish (NFE) AF: 0.000162 AC: 11 AN: 68038

Other (OTH) AF: 0.000946 AC: 2 AN: 2114

Alfa AF: 0.000416 Hom.: 0

Bravo AF: 0.000491

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary spastic paraplegia 8 Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	4.7
DANN	Benign	0.66
PhyloP100		0.62

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: rs188863489; hg19: chr8-126036781;