NM_014846.4:c.3319G>A

Variant names:

• chr8-125032257-C-T
• rs138407503
• NM_014846.4:c.3319G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_014846.4(WASHC5):​c.3319G>A​(p.Val1107Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0035 in 1,614,146 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V1107L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0034 (3 hom., cov: 31)
  • Exomes 𝑓: 0.0035 (12 hom.)
• Consequence: WASHC5 NM_014846.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 2.15
• Publications: 5 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: G2P, ClinGen, Labcorp Genetics (formerly Invitae), 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0075017214).
• BP6: Variant 8-125032257-C-T is Benign according to our data. Variant chr8-125032257-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 188277.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0034 (518/152302) while in subpopulation NFE AF = 0.00467 (318/68032). AF 95% confidence interval is 0.00425. There are 3 homozygotes in GnomAd4. There are 259 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 AR,AD gene

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.3319G>A	p.Val1107Met	missense	Exon 27 of 29	NP_055661.3
	WASHC5	NM_001330609.2		c.2875G>A	p.Val959Met	missense	Exon 26 of 28	NP_001317538.1	E7EQI7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WASHC5	ENST00000318410.12	TSL:1 MANE Select	c.3319G>A	p.Val1107Met	missense	Exon 27 of 29	ENSP00000318016.7	Q12768
	WASHC5	ENST00000920325.1		c.3367G>A	p.Val1123Met	missense	Exon 27 of 29	ENSP00000590384.1
	WASHC5	ENST00000890504.1		c.3319G>A	p.Val1107Met	missense	Exon 28 of 30	ENSP00000560563.1

Frequencies

GnomAD3 genomes AF: 0.00340 AC: 518 AN: 152184 Hom.: 3 Cov.: 31

Gnomad AFR AF: 0.000579

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000981

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0144

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00467

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00406 AC: 1020 AN: 251296 AF XY: 0.00392

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.00266

Gnomad ASJ exome AF: 0.000893

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0137

Gnomad NFE exome AF: 0.00507

Gnomad OTH exome AF: 0.00669

GnomAD4 exome AF: 0.00351 AC: 5130 AN: 1461844 Hom.: 12 Cov.: 31 AF XY: 0.00336 AC XY: 2442 AN XY: 727220

African (AFR) AF: 0.000269 AC: 9 AN: 33478

American (AMR) AF: 0.00239 AC: 107 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000957 AC: 25 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86258

European-Finnish (FIN) AF: 0.0149 AC: 794 AN: 53416

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5764

European-Non Finnish (NFE) AF: 0.00363 AC: 4040 AN: 1111980

Other (OTH) AF: 0.00253 AC: 153 AN: 60394

GnomAD4 genome AF: 0.00340 AC: 518 AN: 152302 Hom.: 3 Cov.: 31 AF XY: 0.00348 AC XY: 259 AN XY: 74474

African (AFR) AF: 0.000577 AC: 24 AN: 41564

American (AMR) AF: 0.000980 AC: 15 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.000865 AC: 3 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.0144 AC: 153 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00467 AC: 318 AN: 68032

Other (OTH) AF: 0.00237 AC: 5 AN: 2112

Alfa AF: 0.00321 Hom.: 3

Bravo AF: 0.00224

TwinsUK AF: 0.00351 AC: 13

ALSPAC AF: 0.00467 AC: 18

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00384 AC: 33

ExAC AF: 0.00444 AC: 539

EpiCase AF: 0.00393

EpiControl AF: 0.00326

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	3	not specified (3)
-	-	1	Hereditary spastic paraplegia (1)
-	-	1	Hereditary spastic paraplegia 8 (1)
-	-	1	Ritscher-Schinzel syndrome;C1863704:Hereditary spastic paraplegia 8 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	18
DANN	Benign	0.96
DEOGEN2	Benign	0.062	T
Eigen	Benign	-0.35
Eigen_PC	Benign	-0.16
FATHMM_MKL	Benign	0.68	D
LIST_S2	Uncertain	0.89	D
MetaRNN	Benign	0.0075	T
MetaSVM	Benign	-0.70	T
PhyloP100		2.1
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.87	N
REVEL	Benign	0.19
Sift	Benign	0.28	T
Sift4G	Benign	0.26	T
Polyphen		0.0	B
Vest4		0.15
MVP		0.73
MPC		0.25
ClinPred		0.020	T
GERP RS		3.0
Varity_R		0.044
gMVP		0.33
Mutation Taster		=98/2	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: rs138407503; hg19: chr8-126044499; COSMIC: COSV59198118;