8-125024791-A-G

Position:

• chr8-125024791-A-G

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.3424-118T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0729 in 721,150 control chromosomes in the GnomAD database, including 2,396 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.063 (437 hom., cov: 31)
  • Exomes 𝑓: 0.075 (1959 hom.)
• Consequence: WASHC5 NM_014846.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.421

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=-0.83).
• BP6: Variant 8-125024791-A-G is Benign according to our data. Variant chr8-125024791-A-G is described in ClinVar as [Benign]. Clinvar id is 1278382.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0879 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
WASHC5	NM_014846.4	c.3424-118T>C		intron_variant		ENST00000318410.12	NP_055661.3
WASHC5	NM_001330609.2	c.2980-118T>C		intron_variant			NP_001317538.1
WASHC5	XM_047422502.1	c.3424-118T>C		intron_variant			XP_047278458.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
WASHC5	ENST00000318410.12	c.3424-118T>C		intron_variant		1	NM_014846.4	ENSP00000318016	P1
WASHC5	ENST00000517845.5	c.2980-118T>C		intron_variant		2		ENSP00000429676
WASHC5	ENST00000519042.2	n.563-118T>C		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.0632 AC: 9601 AN: 151876 Hom.: 437 Cov.: 31

Gnomad AFR AF: 0.0153

Gnomad AMI AF: 0.0824

Gnomad AMR AF: 0.0756

Gnomad ASJ AF: 0.150

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.0238

Gnomad FIN AF: 0.0793

Gnomad MID AF: 0.0696

Gnomad NFE AF: 0.0897

Gnomad OTH AF: 0.0718

GnomAD4 exome AF: 0.0754 AC: 42938 AN: 569156 Hom.: 1959 AF XY: 0.0737 AC XY: 22490 AN XY: 305356

Gnomad4 AFR exome AF: 0.0151

Gnomad4 AMR exome AF: 0.0531

Gnomad4 ASJ exome AF: 0.145

Gnomad4 EAS exome AF: 0.0000627

Gnomad4 SAS exome AF: 0.0240

Gnomad4 FIN exome AF: 0.0811

Gnomad4 NFE exome AF: 0.0915

Gnomad4 OTH exome AF: 0.0771

GnomAD4 genome AF: 0.0632 AC: 9599 AN: 151994 Hom.: 437 Cov.: 31 AF XY: 0.0611 AC XY: 4539 AN XY: 74284

Gnomad4 AFR AF: 0.0152

Gnomad4 AMR AF: 0.0755

Gnomad4 ASJ AF: 0.150

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.0238

Gnomad4 FIN AF: 0.0793

Gnomad4 NFE AF: 0.0897

Gnomad4 OTH AF: 0.0706

Alfa AF: 0.0691 Hom.: 72

Bravo AF: 0.0614

Asia WGS AF: 0.0100 AC: 36 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 26, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	5.7
DANN	Benign	0.73

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: rs17398450; hg19: chr8-126037033;