NM_014846.4:c.1408+7A>G

Variant names:

• chr8-125063515-T-C
• rs16900312
• NM_014846.4:c.1408+7A>G

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.1408+7A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00473 in 1,613,548 control chromosomes in the GnomAD database, including 316 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 (181 hom., cov: 32)
  • Exomes 𝑓: 0.0025 (135 hom.)
• Consequence: WASHC5 NM_014846.4 splice_region, intron
• Scores: Splicing: ADA: 0.0002526
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.143
• Publications: 1 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 (BayesDel_noAF=-0.73).
• BP6: Variant 8-125063515-T-C is Benign according to our data. Variant chr8-125063515-T-C is described in ClinVar as Benign. ClinVar VariationId is 361722.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0899 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WASHC5	NM_014846.4	MANE Select	c.1408+7A>G		splice_region intron	N/A	NP_055661.3
	WASHC5	NM_001330609.2		c.964+7A>G		splice_region intron	N/A	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.1408+7A>G		splice_region intron	N/A	ENSP00000318016.7	Q12768
	WASHC5	ENST00000920325.1		c.1456+7A>G		splice_region intron	N/A	ENSP00000590384.1
	WASHC5	ENST00000890504.1		c.1408+7A>G		splice_region intron	N/A	ENSP00000560563.1

Frequencies

GnomAD3 genomes AF: 0.0263 AC: 4000 AN: 152168 Hom.: 181 Cov.: 32

Gnomad AFR AF: 0.0925

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00838

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

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: 0.00690 AC: 1734 AN: 251336 AF XY: 0.00512

Gnomad AFR exome AF: 0.0958

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: 0.0000792

Gnomad OTH exome AF: 0.00277

GnomAD4 exome AF: 0.00248 AC: 3623 AN: 1461262 Hom.: 135 Cov.: 31 AF XY: 0.00212 AC XY: 1538 AN XY: 726962

African (AFR) AF: 0.0879 AC: 2941 AN: 33456

American (AMR) AF: 0.00496 AC: 222 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26114

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39676

South Asian (SAS) AF: 0.000186 AC: 16 AN: 86248

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53398

Middle Eastern (MID) AF: 0.00347 AC: 20 AN: 5766

European-Non Finnish (NFE) AF: 0.0000693 AC: 77 AN: 1111532

Other (OTH) AF: 0.00573 AC: 346 AN: 60358

GnomAD4 genome AF: 0.0263 AC: 4003 AN: 152286 Hom.: 181 Cov.: 32 AF XY: 0.0255 AC XY: 1900 AN XY: 74476

African (AFR) AF: 0.0923 AC: 3834 AN: 41536

American (AMR) AF: 0.00830 AC: 127 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

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

European-Non Finnish (NFE) AF: 0.000132 AC: 9 AN: 68024

Other (OTH) AF: 0.0132 AC: 28 AN: 2114

Alfa AF: 0.0162 Hom.: 165

Bravo AF: 0.0292

Asia WGS AF: 0.00577 AC: 20 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000178

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	1	Hereditary spastic paraplegia (1)
-	-	1	Hereditary spastic paraplegia 8 (1)
-	-	1	not provided (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	-0.73
CADD	Benign	7.6
DANN	Benign	0.69
PhyloP100		0.14
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00025
dbscSNV1_RF	Benign	0.010
SpliceAI score (max)		0.070		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: rs16900312; hg19: chr8-126075757;