8-125028331-C-T

Variant names:

• chr8-125028331-C-T
• rs7007960
• NM_014846.4:c.3423+289G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_014846.4(WASHC5):​c.3423+289G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.381 in 152,046 control chromosomes in the GnomAD database, including 12,942 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.38 (12942 hom., cov: 32)
• Consequence: WASHC5 NM_014846.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.10
• Publications: 1 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=-0.97).
• BP6: Variant 8-125028331-C-T is Benign according to our data. Variant chr8-125028331-C-T is described in ClinVar as [Benign]. Clinvar id is 683815.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.608 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WASHC5	NM_014846.4	c.3423+289G>A		intron_variant	Intron 28 of 28	ENST00000318410.12	NP_055661.3
WASHC5	NM_001330609.2	c.2979+289G>A		intron_variant	Intron 27 of 27		NP_001317538.1
WASHC5	XM_047422502.1	c.3423+289G>A		intron_variant	Intron 29 of 29		XP_047278458.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WASHC5	ENST00000318410.12	c.3423+289G>A		intron_variant	Intron 28 of 28	1	NM_014846.4	ENSP00000318016.7
WASHC5	ENST00000517845.5	c.2979+289G>A		intron_variant	Intron 26 of 26	2		ENSP00000429676.1
WASHC5	ENST00000519042.2	n.562+289G>A		intron_variant	Intron 2 of 2	2

Frequencies

GnomAD3 genomes AF: 0.380 AC: 57769 AN: 151928 Hom.: 12897 Cov.: 32

Gnomad AFR AF: 0.614

Gnomad AMI AF: 0.0570

Gnomad AMR AF: 0.424

Gnomad ASJ AF: 0.315

Gnomad EAS AF: 0.362

Gnomad SAS AF: 0.455

Gnomad FIN AF: 0.266

Gnomad MID AF: 0.506

Gnomad NFE AF: 0.249

Gnomad OTH AF: 0.379

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.381 AC: 57862 AN: 152046 Hom.: 12942 Cov.: 32 AF XY: 0.387 AC XY: 28744 AN XY: 74320

African (AFR) AF: 0.615 AC: 25460 AN: 41430

American (AMR) AF: 0.424 AC: 6479 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.315 AC: 1093 AN: 3470

East Asian (EAS) AF: 0.360 AC: 1867 AN: 5180

South Asian (SAS) AF: 0.454 AC: 2188 AN: 4822

European-Finnish (FIN) AF: 0.266 AC: 2815 AN: 10576

Middle Eastern (MID) AF: 0.503 AC: 148 AN: 294

European-Non Finnish (NFE) AF: 0.249 AC: 16947 AN: 67964

Other (OTH) AF: 0.386 AC: 813 AN: 2106

Alfa AF: 0.324 Hom.: 1173

Bravo AF: 0.402

Asia WGS AF: 0.485 AC: 1686 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jun 16, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	0.25
DANN	Benign	0.40
PhyloP100		-1.1
Mutation Taster		=100/0	polymorphism (auto)

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: rs7007960; hg19: chr8-126040573;