rs782486251

Variant names:

• chrX-48688919-G-A
• rs782486251
• NM_000377.3:c.1191G>A

Your query was ambiguous. Multiple possible variants found:

• chrX-48688919-G-A
• chrX-48688919-G-C

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_000377.3(WAS):​c.1191G>A​(p.Pro397Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000429 in 1,025,587 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 10 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. P397P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00019 (0 hom., 2 hem., cov: 22)
  • Exomes 𝑓: 0.000026 (0 hom. 8 hem.)
• Consequence: WAS NM_000377.3 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.66
• 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: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.0).
• BP6: Variant X-48688919-G-A is Benign according to our data. Variant chrX-48688919-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 1597253.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.66 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000193 (20/103514) while in subpopulation AFR AF = 0.000697 (20/28689). AF 95% confidence interval is 0.000462. There are 0 homozygotes in GnomAd4. There are 2 alleles in the male GnomAd4 subpopulation. Median coverage is 22. This position passed quality control check.
• BS2: High AC in GnomAd4 at 20 XL,AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000377.3. 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.1191G>A	p.Pro397Pro	synonymous	Exon 10 of 12	NP_000368.1	P42768
	WAS	NM_001438877.1		c.1191G>A	p.Pro397Pro	synonymous	Exon 10 of 12	NP_001425806.1
	WAS	NM_001438878.1		c.1035G>A	p.Pro345Pro	synonymous	Exon 10 of 12	NP_001425807.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WAS	ENST00000376701.5	TSL:1 MANE Select	c.1191G>A	p.Pro397Pro	synonymous	Exon 10 of 12	ENSP00000365891.4	P42768
	WAS	ENST00000698635.1		c.1191G>A	p.Pro397Pro	synonymous	Exon 10 of 12	ENSP00000513850.1	A0A8V8TM35
	WAS	ENST00000698626.1		c.1191G>A	p.Pro397Pro	synonymous	Exon 10 of 13	ENSP00000513845.1	A0A8V8TNH9

Frequencies

GnomAD3 genomes AF: 0.000193 AC: 20 AN: 103456 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.000698

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000612 AC: 6 AN: 98037 AF XY: 0.0000727

Gnomad AFR exome AF: 0.000334

Gnomad AMR exome AF: 0.000158

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000121

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000260 AC: 24 AN: 922073 Hom.: 0 Cov.: 35 AF XY: 0.0000276 AC XY: 8 AN XY: 289753

African (AFR) AF: 0.000327 AC: 7 AN: 21394

American (AMR) AF: 0.000166 AC: 4 AN: 24124

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 13317

East Asian (EAS) AF: 0.0000549 AC: 1 AN: 18227

South Asian (SAS) AF: 0.0000438 AC: 2 AN: 45708

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 24472

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2606

European-Non Finnish (NFE) AF: 0.00000407 AC: 3 AN: 736550

Other (OTH) AF: 0.000196 AC: 7 AN: 35675

GnomAD4 genome AF: 0.000193 AC: 20 AN: 103514 Hom.: 0 Cov.: 22 AF XY: 0.0000682 AC XY: 2 AN XY: 29326

African (AFR) AF: 0.000697 AC: 20 AN: 28689

American (AMR) AF: 0.00 AC: 0 AN: 9821

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2556

East Asian (EAS) AF: 0.00 AC: 0 AN: 2807

South Asian (SAS) AF: 0.00 AC: 0 AN: 1966

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 4886

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 206

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 50535

Other (OTH) AF: 0.00 AC: 0 AN: 1420

Alfa AF: 0.000169 Hom.: 0

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Wiskott-Aldrich syndrome;C1839163:Thrombocytopenia 1;C1845987:X-linked severe congenital neutropenia (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.014
DANN	Benign	0.56
PhyloP100		-2.7
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs782486251; hg19: chrX-48547308;