rs34569226

Variant names:

• chr8-125032351-T-C
• rs34569226
• NM_014846.4:c.3225A>G
• WASHC5 p.Pro1075Pro

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_014846.4(WASHC5):​c.3225A>G​(p.Pro1075Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00231 in 1,614,158 control chromosomes in the GnomAD database, including 63 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.013 (35 hom., cov: 30)
  • Exomes 𝑓: 0.0012 (28 hom.)
• Consequence: WASHC5 NM_014846.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -8.54
• Publications: 2 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: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, ClinGen, G2P
• 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 8-125032351-T-C is Benign according to our data. Variant chr8-125032351-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 361712.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-8.53 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0128 (1950/152298) while in subpopulation AFR AF = 0.0451 (1876/41562). AF 95% confidence interval is 0.0434. There are 35 homozygotes in GnomAd4. There are 932 alleles in the male GnomAd4 subpopulation. Median coverage is 30. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 35 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.3225A>G	p.Pro1075Pro	synonymous	Exon 27 of 29	NP_055661.3
	WASHC5	NM_001330609.2		c.2781A>G	p.Pro927Pro	synonymous	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.3225A>G	p.Pro1075Pro	synonymous	Exon 27 of 29	ENSP00000318016.7	Q12768
	WASHC5	ENST00000920325.1		c.3273A>G	p.Pro1091Pro	synonymous	Exon 27 of 29	ENSP00000590384.1
	WASHC5	ENST00000890504.1		c.3225A>G	p.Pro1075Pro	synonymous	Exon 28 of 30	ENSP00000560563.1

Frequencies

GnomAD3 genomes AF: 0.0128 AC: 1948 AN: 152180 Hom.: 35 Cov.: 30

Gnomad AFR AF: 0.0452

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00353

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00717

GnomAD2 exomes AF: 0.00329 AC: 826 AN: 251140 AF XY: 0.00234

Gnomad AFR exome AF: 0.0457

Gnomad AMR exome AF: 0.00182

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000441

Gnomad OTH exome AF: 0.00229

GnomAD4 exome AF: 0.00122 AC: 1784 AN: 1461860 Hom.: 28 Cov.: 31 AF XY: 0.00100 AC XY: 729 AN XY: 727230

African (AFR) AF: 0.0432 AC: 1446 AN: 33480

American (AMR) AF: 0.00210 AC: 94 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.0000580 AC: 5 AN: 86258

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

Middle Eastern (MID) AF: 0.00243 AC: 14 AN: 5754

European-Non Finnish (NFE) AF: 0.0000414 AC: 46 AN: 1112002

Other (OTH) AF: 0.00296 AC: 179 AN: 60392

GnomAD4 genome AF: 0.0128 AC: 1950 AN: 152298 Hom.: 35 Cov.: 30 AF XY: 0.0125 AC XY: 932 AN XY: 74472

African (AFR) AF: 0.0451 AC: 1876 AN: 41562

American (AMR) AF: 0.00353 AC: 54 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68022

Other (OTH) AF: 0.00710 AC: 15 AN: 2114

Alfa AF: 0.00556 Hom.: 9

Bravo AF: 0.0141

Asia WGS AF: 0.00318 AC: 11 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	1	Hereditary spastic paraplegia (1)
-	-	1	Hereditary spastic paraplegia 8 (1)
-	-	1	Hereditary spastic paraplegia 8;C4551776:Ritscher-Schinzel syndrome 1 (1)
-	-	1	Ritscher-Schinzel syndrome;C1863704:Hereditary spastic paraplegia 8 (1)
-	-	1	WASHC5-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.037
DANN	Benign	0.58
PhyloP100		-8.5
Mutation Taster		=100/0	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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs34569226;

hg19: chr8-126044593;