chr8-125024492-T-C

Variant names:

• chr8-125024492-T-C
• rs539338883
• NM_014846.4:c.*125A>G

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_014846.4(WASHC5):​c.*125A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000372 in 752,434 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000033 (0 hom.)
• Consequence: WASHC5 NM_014846.4 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0300
• 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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WASHC5	NM_014846.4	c.*125A>G		3_prime_UTR_variant	Exon 29 of 29	ENST00000318410.12	NP_055661.3
WASHC5	NM_001330609.2	c.*125A>G		3_prime_UTR_variant	Exon 28 of 28		NP_001317538.1
WASHC5	XM_047422502.1	c.*125A>G		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.*125A>G		3_prime_UTR_variant	Exon 29 of 29	1	NM_014846.4	ENSP00000318016.7
WASHC5	ENST00000519042.2	n.744A>G		non_coding_transcript_exon_variant	Exon 3 of 3	2
WASHC5	ENST00000517845.5	c.*125A>G		3_prime_UTR_variant	Exon 27 of 27	2		ENSP00000429676.1

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 152190 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.000118

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000333 AC: 20 AN: 600244 Hom.: 0 Cov.: 7 AF XY: 0.0000247 AC XY: 8 AN XY: 324300

African (AFR) AF: 0.00 AC: 0 AN: 16766

American (AMR) AF: 0.00 AC: 0 AN: 36590

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20094

East Asian (EAS) AF: 0.00 AC: 0 AN: 34350

South Asian (SAS) AF: 0.00 AC: 0 AN: 64668

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50264

Middle Eastern (MID) AF: 0.000271 AC: 1 AN: 3686

European-Non Finnish (NFE) AF: 0.0000555 AC: 19 AN: 342154

Other (OTH) AF: 0.00 AC: 0 AN: 31672

GnomAD4 genome AF: 0.0000526 AC: 8 AN: 152190 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74352

African (AFR) AF: 0.00 AC: 0 AN: 41448

American (AMR) AF: 0.00 AC: 0 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 68038

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000416

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary spastic paraplegia Uncertain:1

Dec 20, 2016

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Uncertain significance

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
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.82
DANN	Benign	0.59
PhyloP100		-0.030

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: rs539338883; hg19: chr8-126036734;