8-125024659-A-T

Variant names:

• chr8-125024659-A-T
• NM_014846.4:c.3438T>A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_014846.4(WASHC5):​c.3438T>A​(p.His1146Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,458,050 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: WASHC5 NM_014846.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.673

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WASHC5	NM_014846.4	c.3438T>A	p.His1146Gln	missense_variant	Exon 29 of 29	ENST00000318410.12	NP_055661.3
WASHC5	NM_001330609.2	c.2994T>A	p.His998Gln	missense_variant	Exon 28 of 28		NP_001317538.1
WASHC5	XM_047422502.1	c.3438T>A	p.His1146Gln	missense_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.3438T>A	p.His1146Gln	missense_variant	Exon 29 of 29	1	NM_014846.4	ENSP00000318016.7
WASHC5	ENST00000517845.5	c.2994T>A	p.His998Gln	missense_variant	Exon 27 of 27	2		ENSP00000429676.1
WASHC5	ENST00000519042.2	n.577T>A		non_coding_transcript_exon_variant	Exon 3 of 3	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1458050 Hom.: 0 Cov.: 27 AF XY: 0.00000138 AC XY: 1 AN XY: 725602

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.40
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.10
CADD	Benign	11
DANN	Benign	0.97
DEOGEN2	Benign	0.29	T;.
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.37
FATHMM_MKL	Benign	0.47	N
LIST_S2	Uncertain	0.88	D;D
M_CAP	Benign	0.064	D
MetaRNN	Uncertain	0.66	D;D
MetaSVM	Uncertain	0.14	D
PrimateAI	Pathogenic	0.79	T
PROVEAN	Uncertain	-2.7	D;D
REVEL	Uncertain	0.59
Sift	Benign	0.074	T;D
Sift4G	Benign	0.22	T;T
Polyphen		0.93	P;.
Vest4		0.77
MutPred		0.43		Gain of relative solvent accessibility (P = 0.0999);.;
MVP		0.79
MPC		0.28
ClinPred		0.94	D
GERP RS		-4.1
Varity_R		0.34
gMVP		0.64

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr8-126036901;