rs1409607754

Variant names:

• chrX-48688808-A-C
• rs1409607754
• NM_000377.3:c.1080A>C

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_001438878.1(WAS):​c.932-8A>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0016 (0 hom., 0 hem., cov: 12)
  • Exomes 𝑓: 0.00042 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: WAS NM_001438878.1 splice_region, intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:2
• Conservation: PhyloP100: -0.0100
• Publications: 0 publications found

Genes affected

WAS (HGNC:12731): (WASP actin nucleation promoting factor) The Wiskott-Aldrich syndrome (WAS) family of proteins share similar domain structure, and are involved in transduction of signals from receptors on the cell surface to the actin cytoskeleton. The presence of a number of different motifs suggests that they are regulated by a number of different stimuli, and interact with multiple proteins. Recent studies have demonstrated that these proteins, directly or indirectly, associate with the small GTPase, Cdc42, known to regulate formation of actin filaments, and the cytoskeletal organizing complex, Arp2/3. Wiskott-Aldrich syndrome is a rare, inherited, X-linked, recessive disease characterized by immune dysregulation and microthrombocytopenia, and is caused by mutations in the WAS gene. The WAS gene product is a cytoplasmic protein, expressed exclusively in hematopoietic cells, which show signalling and cytoskeletal abnormalities in WAS patients. A transcript variant arising as a result of alternative promoter usage, and containing a different 5' UTR sequence, has been described, however, its full-length nature is not known. [provided by RefSeq, Jul 2008]

WAS Gene-Disease associations (from GenCC):

• Wiskott-Aldrich syndrome

  Inheritance: XL, AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Orphanet, Ambry Genetics
• X-linked severe congenital neutropenia

  Inheritance: XL Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics
• thrombocytopenia 1

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000232828 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.59).
• BP6: Variant X-48688808-A-C is Benign according to our data. Variant chrX-48688808-A-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 437265.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001438878.1. 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
	WAS	NM_000377.3	MANE Select	c.1080A>C	p.Pro360Pro	synonymous	Exon 10 of 12	NP_000368.1	P42768
	WAS	NM_001438877.1		c.1080A>C	p.Pro360Pro	synonymous	Exon 10 of 12	NP_001425806.1
	WAS	NM_001438879.1		c.1080A>C	p.Pro360Pro	synonymous	Exon 11 of 13	NP_001425808.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WAS	ENST00000376701.5	TSL:1 MANE Select	c.1080A>C	p.Pro360Pro	synonymous	Exon 10 of 12	ENSP00000365891.4	P42768
	WAS	ENST00000698635.1		c.1080A>C	p.Pro360Pro	synonymous	Exon 10 of 12	ENSP00000513850.1	A0A8V8TM35
	WAS	ENST00000698626.1		c.1080A>C	p.Pro360Pro	synonymous	Exon 10 of 13	ENSP00000513845.1	A0A8V8TNH9

Frequencies

GnomAD3 genomes AF: 0.00159 AC: 80 AN: 50322 Hom.: 0 Cov.: 12

Gnomad AFR AF: 0.00144

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00168

Gnomad ASJ AF: 0.000803

Gnomad EAS AF: 0.00179

Gnomad SAS AF: 0.00297

Gnomad FIN AF: 0.00329

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00155

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000119 AC: 8 AN: 67228 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000974

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000557

Gnomad NFE exome AF: 0.0000779

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000416 AC: 260 AN: 625176 Hom.: 0 Cov.: 25 AF XY: 0.00 AC XY: 0 AN XY: 180036

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000600 AC: 9 AN: 15006

American (AMR) AF: 0.00106 AC: 15 AN: 14138

Ashkenazi Jewish (ASJ) AF: 0.000914 AC: 8 AN: 8748

East Asian (EAS) AF: 0.000924 AC: 12 AN: 12982

South Asian (SAS) AF: 0.000368 AC: 11 AN: 29886

European-Finnish (FIN) AF: 0.000941 AC: 21 AN: 22311

Middle Eastern (MID) AF: 0.00347 AC: 5 AN: 1440

European-Non Finnish (NFE) AF: 0.000323 AC: 160 AN: 496099

Other (OTH) AF: 0.000773 AC: 19 AN: 24566

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00161 AC: 81 AN: 50340 Hom.: 0 Cov.: 12 AF XY: 0.00 AC XY: 0 AN XY: 12606

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00151 AC: 20 AN: 13261

American (AMR) AF: 0.00168 AC: 9 AN: 5363

Ashkenazi Jewish (ASJ) AF: 0.000803 AC: 1 AN: 1246

East Asian (EAS) AF: 0.00180 AC: 3 AN: 1668

South Asian (SAS) AF: 0.00298 AC: 3 AN: 1007

European-Finnish (FIN) AF: 0.00329 AC: 7 AN: 2128

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 145

European-Non Finnish (NFE) AF: 0.00155 AC: 38 AN: 24514

Other (OTH) AF: 0.00 AC: 0 AN: 755

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0506 Hom.: 1

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	not provided (2)
-	1	-	not specified (1)
-	-	1	Wiskott-Aldrich syndrome;C1839163:Thrombocytopenia 1;C1845987:X-linked severe congenital neutropenia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
CADD	Benign	9.3
DANN	Benign	0.59
PhyloP100		-0.010
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs1409607754; hg19: chrX-48547197; COSMIC: COSV64997936; COSMIC: COSV64997936;