rs1815967070

Variant names:

• chr8-125043826-T-C
• rs1815967070
• NM_014846.4:c.2849A>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_014846.4(WASHC5):​c.2849A>G​(p.Lys950Arg) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: WASHC5 NM_014846.4 missense, splice_region
• Scores: Splicing: ADA: 0.9993
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 7.95
• Publications: 1 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-AS1 (HGNC:43440): (WASHC5 antisense RNA 1)

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

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.2849A>G	p.Lys950Arg	missense splice_region	Exon 23 of 29	NP_055661.3
	WASHC5	NM_001330609.2		c.2405A>G	p.Lys802Arg	missense splice_region	Exon 22 of 28	NP_001317538.1	E7EQI7
	WASHC5-AS1	NR_170219.1		n.97-673T>C		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WASHC5	ENST00000318410.12	TSL:1 MANE Select	c.2849A>G	p.Lys950Arg	missense splice_region	Exon 23 of 29	ENSP00000318016.7	Q12768
	WASHC5	ENST00000920325.1		c.2897A>G	p.Lys966Arg	missense splice_region	Exon 23 of 29	ENSP00000590384.1
	WASHC5	ENST00000890504.1		c.2849A>G	p.Lys950Arg	missense splice_region	Exon 24 of 30	ENSP00000560563.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Hereditary spastic paraplegia 8 (1)
-	1	-	Ritscher-Schinzel syndrome 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.060
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.37	T
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.043	D
MetaRNN	Uncertain	0.62	D
MetaSVM	Benign	-0.89	T
PhyloP100		7.9
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-1.0	N
REVEL	Uncertain	0.62
Sift	Benign	0.31	T
Sift4G	Benign	0.42	T
Polyphen		0.98	D
Vest4		0.78
MutPred		0.48		Gain of MoRF binding (P = 0.0677)
MVP		0.90
MPC		0.28
ClinPred		0.84	D
GERP RS		5.3
Varity_R		0.19
gMVP		0.58
Mutation Taster		=53/47	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.99
SpliceAI score (max)		0.15		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: rs1815967070; hg19: chr8-126056068;