8-125024791-A-G

Variant names:

• chr8-125024791-A-G
• rs17398450
• NM_014846.4:c.3424-118T>C

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.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
• Publications: 3 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 8-125024791-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 rank	MANE	Protein	UniProt
WASHC5	NM_014846.4	c.3424-118T>C		intron_variant	Intron 28 of 28	ENST00000318410.12	NP_055661.3
WASHC5	NM_001330609.2	c.2980-118T>C		intron_variant	Intron 27 of 27		NP_001317538.1
WASHC5	XM_047422502.1	c.3424-118T>C		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.3424-118T>C		intron_variant	Intron 28 of 28	1	NM_014846.4	ENSP00000318016.7
WASHC5	ENST00000517845.5	c.2980-118T>C		intron_variant	Intron 26 of 26	2		ENSP00000429676.1
WASHC5	ENST00000519042.2	n.563-118T>C		intron_variant	Intron 2 of 2	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

African (AFR) AF: 0.0151 AC: 225 AN: 14918

American (AMR) AF: 0.0531 AC: 1635 AN: 30790

Ashkenazi Jewish (ASJ) AF: 0.145 AC: 2719 AN: 18704

East Asian (EAS) AF: 0.0000627 AC: 2 AN: 31880

South Asian (SAS) AF: 0.0240 AC: 1404 AN: 58586

European-Finnish (FIN) AF: 0.0811 AC: 3798 AN: 46822

Middle Eastern (MID) AF: 0.0772 AC: 181 AN: 2344

European-Non Finnish (NFE) AF: 0.0915 AC: 30664 AN: 335158

Other (OTH) AF: 0.0771 AC: 2310 AN: 29954

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

African (AFR) AF: 0.0152 AC: 632 AN: 41486

American (AMR) AF: 0.0755 AC: 1151 AN: 15248

Ashkenazi Jewish (ASJ) AF: 0.150 AC: 520 AN: 3466

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5148

South Asian (SAS) AF: 0.0238 AC: 115 AN: 4826

European-Finnish (FIN) AF: 0.0793 AC: 833 AN: 10508

Middle Eastern (MID) AF: 0.0714 AC: 21 AN: 294

European-Non Finnish (NFE) AF: 0.0897 AC: 6102 AN: 67998

Other (OTH) AF: 0.0706 AC: 149 AN: 2110

Alfa AF: 0.0689 Hom.: 75

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

Jun 26, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	5.7
DANN	Benign	0.73
PhyloP100		0.42
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: rs17398450; hg19: chr8-126037033;