8-125024576-AT-A

Variant names:

• chr8-125024576-AT-A
• rs550928439
• NM_014846.4:c.*40delA

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.*40delA variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00128 in 1,405,236 control chromosomes in the GnomAD database, including 3 homozygotes. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00074 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0013 (3 hom.)
• Consequence: WASHC5 NM_014846.4 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.111
• 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 8-125024576-AT-A is Benign according to our data. Variant chr8-125024576-AT-A is described in ClinVar as [Likely_benign]. Clinvar id is 361709.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000742 (113/152328) while in subpopulation AMR AF = 0.00111 (17/15304). AF 95% confidence interval is 0.000821. There are 0 homozygotes in GnomAd4. There are 57 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 3 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WASHC5	NM_014846.4	c.*40delA		3_prime_UTR_variant	Exon 29 of 29	ENST00000318410.12	NP_055661.3
WASHC5	NM_001330609.2	c.*40delA		3_prime_UTR_variant	Exon 28 of 28		NP_001317538.1
WASHC5	XM_047422502.1	c.*40delA		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.*40delA		3_prime_UTR_variant	Exon 29 of 29	1	NM_014846.4	ENSP00000318016.7
WASHC5	ENST00000519042.2	n.659delA		non_coding_transcript_exon_variant	Exon 3 of 3	2
WASHC5	ENST00000517845.5	c.*40delA		3_prime_UTR_variant	Exon 27 of 27	2		ENSP00000429676.1

Frequencies

GnomAD3 genomes AF: 0.000742 AC: 113 AN: 152210 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00111

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00122

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00101

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.000921 AC: 230 AN: 249816 AF XY: 0.000852

Gnomad AFR exome AF: 0.000126

Gnomad AMR exome AF: 0.00169

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00153

Gnomad NFE exome AF: 0.00112

Gnomad OTH exome AF: 0.00148

GnomAD4 exome AF: 0.00135 AC: 1691 AN: 1252908 Hom.: 3 Cov.: 19 AF XY: 0.00134 AC XY: 852 AN XY: 634172

African (AFR) AF: 0.0000677 AC: 2 AN: 29532

American (AMR) AF: 0.00185 AC: 82 AN: 44350

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24786

East Asian (EAS) AF: 0.00 AC: 0 AN: 38684

South Asian (SAS) AF: 0.0000609 AC: 5 AN: 82056

European-Finnish (FIN) AF: 0.00128 AC: 68 AN: 53302

Middle Eastern (MID) AF: 0.000556 AC: 3 AN: 5394

European-Non Finnish (NFE) AF: 0.00159 AC: 1461 AN: 921326

Other (OTH) AF: 0.00131 AC: 70 AN: 53478

GnomAD4 genome AF: 0.000742 AC: 113 AN: 152328 Hom.: 0 Cov.: 32 AF XY: 0.000765 AC XY: 57 AN XY: 74498

African (AFR) AF: 0.000240 AC: 10 AN: 41580

American (AMR) AF: 0.00111 AC: 17 AN: 15304

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00122 AC: 13 AN: 10626

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00101 AC: 69 AN: 68022

Other (OTH) AF: 0.00142 AC: 3 AN: 2112

Alfa AF: 0.00104 Hom.: 0

Bravo AF: 0.000907

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		0.11
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: rs550928439; hg19: chr8-126036818;