rs199912701

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: Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae), ClinGen
• hereditary spastic paraplegia 8

  Inheritance: AD Classification: MODERATE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• 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 VariationId 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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014846.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WASHC5	NM_014846.4	MANE Select	c.*269_*270delGT		3_prime_UTR	Exon 29 of 29	NP_055661.3
	WASHC5	NM_001330609.2		c.*269_*270delGT		3_prime_UTR	Exon 28 of 28	NP_001317538.1	E7EQI7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WASHC5	ENST00000318410.12	TSL:1 MANE Select	c.*269_*270delGT		3_prime_UTR	Exon 29 of 29	ENSP00000318016.7	Q12768
	WASHC5	ENST00000920325.1		c.*269_*270delGT		3_prime_UTR	Exon 29 of 29	ENSP00000590384.1
	WASHC5	ENST00000890504.1		c.*269_*270delGT		3_prime_UTR	Exon 30 of 30	ENSP00000560563.1

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

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Spastic paraplegia, autosomal dominant (1)

Computational scores

Source: dbNSFP v4.9

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;