8-125024346-AAC-A

Variant names:

• chr8-125024346-AAC-A
• rs199912701
• NM_014846.4:c.*269_*270delGT

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The NM_014846.4(WASHC5):​c.*269_*270delGT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00285 in 514,106 control chromosomes in the GnomAD database, including 9 homozygotes. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0074 (8 hom., cov: 32)
  • Exomes 𝑓: 0.00091 (1 hom.)
• Consequence: WASHC5 NM_014846.4 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.10
• 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 -10 ACMG points.

• BP6: Variant 8-125024346-AAC-A is Benign according to our data. Variant chr8-125024346-AAC-A is described in ClinVar as [Likely_benign]. Clinvar id is 361706.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00744 (1134/152342) while in subpopulation AFR AF = 0.0256 (1064/41562). AF 95% confidence interval is 0.0243. There are 8 homozygotes in GnomAd4. There are 536 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 8 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WASHC5	NM_014846.4	c.*269_*270delGT		3_prime_UTR_variant	Exon 29 of 29	ENST00000318410.12	NP_055661.3
WASHC5	NM_001330609.2	c.*269_*270delGT		3_prime_UTR_variant	Exon 28 of 28		NP_001317538.1
WASHC5	XM_047422502.1	c.*269_*270delGT		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.*269_*270delGT		3_prime_UTR_variant	Exon 29 of 29	1	NM_014846.4	ENSP00000318016.7
WASHC5	ENST00000519042.2	n.888_889delGT		non_coding_transcript_exon_variant	Exon 3 of 3	2
WASHC5	ENST00000517845.5	c.*269_*270delGT		3_prime_UTR_variant	Exon 27 of 27	2		ENSP00000429676.1

Frequencies

GnomAD3 genomes AF: 0.00744 AC: 1133 AN: 152224 Hom.: 8 Cov.: 32

Gnomad AFR AF: 0.0257

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00314

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00716

GnomAD4 exome AF: 0.000915 AC: 331 AN: 361764 Hom.: 1 AF XY: 0.000754 AC XY: 145 AN XY: 192238

African (AFR) AF: 0.0241 AC: 252 AN: 10476

American (AMR) AF: 0.00220 AC: 35 AN: 15900

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 10752

East Asian (EAS) AF: 0.00 AC: 0 AN: 22842

South Asian (SAS) AF: 0.000196 AC: 8 AN: 40826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 23764

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1546

European-Non Finnish (NFE) AF: 0.0000372 AC: 8 AN: 215082

Other (OTH) AF: 0.00136 AC: 28 AN: 20576

GnomAD4 genome AF: 0.00744 AC: 1134 AN: 152342 Hom.: 8 Cov.: 32 AF XY: 0.00720 AC XY: 536 AN XY: 74494

African (AFR) AF: 0.0256 AC: 1064 AN: 41562

American (AMR) AF: 0.00313 AC: 48 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

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

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 68036

Other (OTH) AF: 0.00709 AC: 15 AN: 2116

Alfa AF: 0.00512 Hom.: 1

Bravo AF: 0.00842

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Spastic paraplegia, autosomal dominant Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.1
Mutation Taster		=100/0	polymorphism

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: rs199912701; hg19: chr8-126036588;