NM_014846.4:c.3423+237C>T

Variant names:

• chr8-125028383-G-A
• rs57886679
• NM_014846.4:c.3423+237C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_014846.4(WASHC5):​c.3423+237C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.106 in 152,178 control chromosomes in the GnomAD database, including 999 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.11 (999 hom., cov: 32)
• Consequence: WASHC5 NM_014846.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0170
• 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 Gene-Disease associations (from GenCC):

• Ritscher-Schinzel syndrome 1

  Inheritance: AR Classification: STRONG, LIMITED Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), G2P, 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 8-125028383-G-A is Benign according to our data. Variant chr8-125028383-G-A is described in ClinVar as [Benign]. Clinvar id is 1293644.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.16 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WASHC5	NM_014846.4	c.3423+237C>T		intron_variant	Intron 28 of 28	ENST00000318410.12	NP_055661.3
WASHC5	NM_001330609.2	c.2979+237C>T		intron_variant	Intron 27 of 27		NP_001317538.1
WASHC5	XM_047422502.1	c.3423+237C>T		intron_variant	Intron 29 of 29		XP_047278458.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WASHC5	ENST00000318410.12	c.3423+237C>T		intron_variant	Intron 28 of 28	1	NM_014846.4	ENSP00000318016.7
WASHC5	ENST00000517845.5	c.2979+237C>T		intron_variant	Intron 26 of 26	2		ENSP00000429676.1
WASHC5	ENST00000519042.2	n.562+237C>T		intron_variant	Intron 2 of 2	2

Frequencies

GnomAD3 genomes AF: 0.106 AC: 16070 AN: 152060 Hom.: 998 Cov.: 32

Gnomad AFR AF: 0.163

Gnomad AMI AF: 0.0833

Gnomad AMR AF: 0.0944

Gnomad ASJ AF: 0.136

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0244

Gnomad FIN AF: 0.0790

Gnomad MID AF: 0.0791

Gnomad NFE AF: 0.0900

Gnomad OTH AF: 0.110

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.106 AC: 16077 AN: 152178 Hom.: 999 Cov.: 32 AF XY: 0.102 AC XY: 7602 AN XY: 74402

African (AFR) AF: 0.163 AC: 6764 AN: 41506

American (AMR) AF: 0.0942 AC: 1441 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.136 AC: 471 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5180

South Asian (SAS) AF: 0.0245 AC: 118 AN: 4824

European-Finnish (FIN) AF: 0.0790 AC: 836 AN: 10586

Middle Eastern (MID) AF: 0.0816 AC: 24 AN: 294

European-Non Finnish (NFE) AF: 0.0900 AC: 6118 AN: 68004

Other (OTH) AF: 0.108 AC: 228 AN: 2110

Alfa AF: 0.106 Hom.: 150

Bravo AF: 0.110

Asia WGS AF: 0.0190 AC: 65 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jun 26, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	3.3
DANN	Benign	0.64
PhyloP100		-0.017
Mutation Taster		=100/0	polymorphism (auto)

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: rs57886679; hg19: chr8-126040625;