8-125067727-C-T

Variant names:

• chr8-125067727-C-T
• rs16900335
• NM_014846.4:c.1151-8G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_014846.4(WASHC5):​c.1151-8G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0047 in 1,613,160 control chromosomes in the GnomAD database, including 313 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.026 (179 hom., cov: 32)
  • Exomes 𝑓: 0.0025 (134 hom.)
• Consequence: WASHC5 NM_014846.4 splice_region, intron
• Scores: Splicing: ADA: 0.00004255
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -2.89
• 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: 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.0).
• BP6: Variant 8-125067727-C-T is Benign according to our data. Variant chr8-125067727-C-T is described in ClinVar as Benign. ClinVar VariationId is 361727.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0897 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WASHC5	NM_014846.4	MANE Select	c.1151-8G>A		splice_region intron	N/A	NP_055661.3
	WASHC5	NM_001330609.2		c.707-8G>A		splice_region intron	N/A	NP_001317538.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WASHC5	ENST00000318410.12	TSL:1 MANE Select	c.1151-8G>A		splice_region intron	N/A	ENSP00000318016.7
	WASHC5	ENST00000517845.5	TSL:2	c.707-8G>A		splice_region intron	N/A	ENSP00000429676.1

Frequencies

GnomAD3 genomes AF: 0.0262 AC: 3986 AN: 151970 Hom.: 179 Cov.: 32

Gnomad AFR AF: 0.0923

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00845

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.0134

GnomAD2 exomes AF: 0.00688 AC: 1729 AN: 251424 AF XY: 0.00511

Gnomad AFR exome AF: 0.0955

Gnomad AMR exome AF: 0.00422

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000791

Gnomad OTH exome AF: 0.00277

GnomAD4 exome AF: 0.00246 AC: 3598 AN: 1461072 Hom.: 134 Cov.: 31 AF XY: 0.00210 AC XY: 1529 AN XY: 726848

African (AFR) AF: 0.0874 AC: 2920 AN: 33406

American (AMR) AF: 0.00497 AC: 222 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26106

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39646

South Asian (SAS) AF: 0.000186 AC: 16 AN: 86224

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53346

Middle Eastern (MID) AF: 0.00347 AC: 20 AN: 5764

European-Non Finnish (NFE) AF: 0.0000684 AC: 76 AN: 1111506

Other (OTH) AF: 0.00568 AC: 343 AN: 60364

GnomAD4 genome AF: 0.0262 AC: 3989 AN: 152088 Hom.: 179 Cov.: 32 AF XY: 0.0254 AC XY: 1885 AN XY: 74358

African (AFR) AF: 0.0921 AC: 3819 AN: 41456

American (AMR) AF: 0.00837 AC: 128 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4810

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10584

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.000132 AC: 9 AN: 67986

Other (OTH) AF: 0.0133 AC: 28 AN: 2112

Alfa AF: 0.0127 Hom.: 42

Bravo AF: 0.0292

Asia WGS AF: 0.00577 AC: 20 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Hereditary spastic paraplegia (1)
-	-	1	Hereditary spastic paraplegia 8 (1)
-	-	1	not provided (1)
-	-	1	not specified (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	-1.0
CADD	Benign	0.0010
DANN	Benign	0.47
PhyloP100		-2.9
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000043
dbscSNV1_RF	Benign	0.0020
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: rs16900335; hg19: chr8-126079969;