8-125028331-C-T

Position:

• chr8-125028331-C-T

Variant summary

Our verdict is Benign. Variant got -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

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]

ACMG classification

Verdict is Benign. Variant got -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/exons	MANE	UniProt
WASHC5	NM_014846.4	c.3423+289G>A		intron_variant		ENST00000318410.12
WASHC5	NM_001330609.2	c.2979+289G>A		intron_variant
WASHC5	XM_047422502.1	c.3423+289G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WASHC5	ENST00000318410.12	c.3423+289G>A		intron_variant		1	NM_014846.4	P1
WASHC5	ENST00000517845.5	c.2979+289G>A		intron_variant		2
WASHC5	ENST00000519042.2	n.562+289G>A		intron_variant, non_coding_transcript_variant		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

Gnomad4 AFR AF: 0.615

Gnomad4 AMR AF: 0.424

Gnomad4 ASJ AF: 0.315

Gnomad4 EAS AF: 0.360

Gnomad4 SAS AF: 0.454

Gnomad4 FIN AF: 0.266

Gnomad4 NFE AF: 0.249

Gnomad4 OTH AF: 0.386

Alfa AF: 0.312 Hom.: 1034

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

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 16, 2018

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

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

Other links and lift over

dbSNP: rs7007960; hg19: chr8-126040573;