8-125043839-C-G

Variant names:

• chr8-125043839-C-G
• rs534139966
• NM_014846.4:c.2836G>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_014846.4(WASHC5):​c.2836G>C​(p.Glu946Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 1,457,346 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E946K) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: WASHC5 NM_014846.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.84
• 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-AS1 (HGNC:43440): (WASHC5 antisense RNA 1)

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.2836G>C	p.Glu946Gln	missense	Exon 23 of 29	NP_055661.3
	WASHC5	NM_001330609.2		c.2392G>C	p.Glu798Gln	missense	Exon 22 of 28	NP_001317538.1	E7EQI7
	WASHC5-AS1	NR_170219.1		n.97-660C>G		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WASHC5	ENST00000318410.12	TSL:1 MANE Select	c.2836G>C	p.Glu946Gln	missense	Exon 23 of 29	ENSP00000318016.7	Q12768
	WASHC5	ENST00000920325.1		c.2884G>C	p.Glu962Gln	missense	Exon 23 of 29	ENSP00000590384.1
	WASHC5	ENST00000890504.1		c.2836G>C	p.Glu946Gln	missense	Exon 24 of 30	ENSP00000560563.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1457346 Hom.: 0 Cov.: 29 AF XY: 0.00000276 AC XY: 2 AN XY: 725340

African (AFR) AF: 0.00 AC: 0 AN: 33370

American (AMR) AF: 0.0000224 AC: 1 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26104

East Asian (EAS) AF: 0.00 AC: 0 AN: 39650

South Asian (SAS) AF: 0.00 AC: 0 AN: 86150

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53408

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5756

European-Non Finnish (NFE) AF: 0.00000181 AC: 2 AN: 1107992

Other (OTH) AF: 0.00 AC: 0 AN: 60206

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.35
BayesDel_addAF	Uncertain	0.082	D
BayesDel_noAF	Benign	-0.12
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.64	D
Eigen	Uncertain	0.32
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.94	D
M_CAP	Uncertain	0.095	D
MetaRNN	Uncertain	0.49	T
MetaSVM	Uncertain	0.31	D
PhyloP100		7.8
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-1.7	N
REVEL	Uncertain	0.53
Sift	Uncertain	0.022	D
Sift4G	Benign	0.098	T
Polyphen		0.22	B
Vest4		0.44
MutPred		0.62		Gain of MoRF binding (P = 0.0194)
MVP		0.85
MPC		0.65
ClinPred		0.97	D
GERP RS		5.3
Varity_R		0.19
gMVP		0.44
Mutation Taster		=69/31	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: rs534139966; hg19: chr8-126056081;