rs372649110

Variant names:

• chrX-48689027-G-A
• rs372649110
• NM_000377.3:c.1299G>A

Your query was ambiguous. Multiple possible variants found:

• chrX-48689027-G-A
• chrX-48689027-G-T

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_001438877.1(WAS):​c.1299G>A​(p.Ala433Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00134 in 1,203,318 control chromosomes in the GnomAD database, including 15 homozygotes. There are 876 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. A433A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00080 (1 hom., 42 hem., cov: 23)
  • Exomes 𝑓: 0.0014 (14 hom. 834 hem.)
• Consequence: WAS NM_001438877.1 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -2.42
• Publications: 1 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: ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet
• X-linked severe congenital neutropenia

  Inheritance: XL Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet
• 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=-0.7).
• BP6: Variant X-48689027-G-A is Benign according to our data. Variant chrX-48689027-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 212587.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.42 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000798 (89/111505) while in subpopulation SAS AF = 0.0315 (84/2670). AF 95% confidence interval is 0.026. There are 1 homozygotes in GnomAd4. There are 42 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.
• BS2: High AC in GnomAd4 at 89 XL,AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001438877.1. 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.1299G>A	p.Ala433Ala	synonymous	Exon 10 of 12	NP_000368.1
	WAS	NM_001438877.1		c.1299G>A	p.Ala433Ala	synonymous	Exon 10 of 12	NP_001425806.1
	WAS	NM_001438878.1		c.1143G>A	p.Ala381Ala	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.1299G>A	p.Ala433Ala	synonymous	Exon 10 of 12	ENSP00000365891.4
	WAS	ENST00000698635.1		c.1299G>A	p.Ala433Ala	synonymous	Exon 10 of 12	ENSP00000513850.1
	WAS	ENST00000698626.1		c.1299G>A	p.Ala433Ala	synonymous	Exon 10 of 13	ENSP00000513845.1

Frequencies

GnomAD3 genomes AF: 0.000799 AC: 89 AN: 111457 Hom.: 1 Cov.: 23

Gnomad AFR AF: 0.000131

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0314

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000189

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00303 AC: 499 AN: 164688 AF XY: 0.00474

Gnomad AFR exome AF: 0.000184

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000153

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000546

Gnomad OTH exome AF: 0.000239

GnomAD4 exome AF: 0.00140 AC: 1528 AN: 1091813 Hom.: 14 Cov.: 33 AF XY: 0.00232 AC XY: 834 AN XY: 359569

African (AFR) AF: 0.0000758 AC: 2 AN: 26375

American (AMR) AF: 0.00 AC: 0 AN: 35007

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19336

East Asian (EAS) AF: 0.0000995 AC: 3 AN: 30152

South Asian (SAS) AF: 0.0262 AC: 1405 AN: 53599

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 36230

Middle Eastern (MID) AF: 0.000489 AC: 2 AN: 4086

European-Non Finnish (NFE) AF: 0.0000297 AC: 25 AN: 841063

Other (OTH) AF: 0.00198 AC: 91 AN: 45965

GnomAD4 genome AF: 0.000798 AC: 89 AN: 111505 Hom.: 1 Cov.: 23 AF XY: 0.00125 AC XY: 42 AN XY: 33735

African (AFR) AF: 0.000130 AC: 4 AN: 30705

American (AMR) AF: 0.00 AC: 0 AN: 10622

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2641

East Asian (EAS) AF: 0.00 AC: 0 AN: 3503

South Asian (SAS) AF: 0.0315 AC: 84 AN: 2670

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6075

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 212

European-Non Finnish (NFE) AF: 0.0000189 AC: 1 AN: 52892

Other (OTH) AF: 0.00 AC: 0 AN: 1507

Alfa AF: 0.000521 Hom.: 2

Bravo AF: 0.000230

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not specified (2)
-	-	1	not provided (1)
-	-	1	Wiskott-Aldrich syndrome (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	-0.70
CADD	Benign	0.34
DANN	Benign	0.75
PhyloP100		-2.4
Mutation Taster		=100/0	polymorphism (auto)

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: rs372649110; hg19: chrX-48547416; COSMIC: COSV64997394; COSMIC: COSV64997394;