NM_014846.4:c.2003G>T

Variant names:

• chr8-125056690-C-A
• rs763639768
• NM_014846.4:c.2003G>T

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP4

The NM_014846.4(WASHC5):​c.2003G>T​(p.Gly668Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000041 in 1,461,824 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (1 hom.)
• Consequence: WASHC5 NM_014846.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 1.24
• 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 -1 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.29545015).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WASHC5	NM_014846.4	MANE Select	c.2003G>T	p.Gly668Val	missense	Exon 16 of 29	NP_055661.3
	WASHC5	NM_001330609.2		c.1559G>T	p.Gly520Val	missense	Exon 15 of 28	NP_001317538.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WASHC5	ENST00000318410.12	TSL:1 MANE Select	c.2003G>T	p.Gly668Val	missense	Exon 16 of 29	ENSP00000318016.7
	WASHC5	ENST00000920325.1		c.2051G>T	p.Gly684Val	missense	Exon 16 of 29	ENSP00000590384.1
	WASHC5	ENST00000890504.1		c.2003G>T	p.Gly668Val	missense	Exon 17 of 30	ENSP00000560563.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000410 AC: 6 AN: 1461824 Hom.: 1 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727216

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00000450 AC: 5 AN: 1111962

Other (OTH) AF: 0.0000166 AC: 1 AN: 60390

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)
-	1	-	Ritscher-Schinzel syndrome;C1863704:Hereditary spastic paraplegia 8 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Uncertain	0.045	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	20
DANN	Benign	0.96
DEOGEN2	Uncertain	0.51	D
Eigen	Benign	-0.46
Eigen_PC	Benign	-0.35
FATHMM_MKL	Benign	0.67	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.063	D
MetaRNN	Benign	0.30	T
MetaSVM	Benign	-0.49	T
PhyloP100		1.2
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-1.9	N
REVEL	Uncertain	0.31
Sift	Benign	0.049	D
Sift4G	Uncertain	0.018	D
Polyphen		0.0	B
Vest4		0.47
MutPred		0.61		Gain of helix (P = 0.0425)
MVP		0.63
MPC		0.30
ClinPred		0.37	T
GERP RS		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.17
gMVP		0.65
Mutation Taster		=88/12	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: rs763639768; hg19: chr8-126068932;