rs146220228

Variant names:

• chrX-48685764-G-A
• rs146220228
• NM_000377.3:c.391G>A

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 2P and 13B. PM1 BP4_Strong BP6 BS1 BS2

The NM_000377.3(WAS):​c.391G>A​(p.Glu131Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00265 in 1,180,777 control chromosomes in the GnomAD database, including 5 homozygotes. There are 978 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0022 (1 hom., 77 hem., cov: 23)
  • Exomes 𝑓: 0.0027 (4 hom. 901 hem.)
• Consequence: WAS NM_000377.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:8 O:1
• Conservation: PhyloP100: 1.61
• Publications: 10 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 -11 ACMG points.

• PM1: In a hotspot region, there are 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 7 uncertain in NM_000377.3
• BP4: Computational evidence support a benign effect (MetaRNN=0.0077780485).
• BP6: Variant X-48685764-G-A is Benign according to our data. Variant chrX-48685764-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 135413.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00217 (244/112368) while in subpopulation NFE AF = 0.00336 (179/53264). AF 95% confidence interval is 0.00296. There are 1 homozygotes in GnomAd4. There are 77 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.
• BS2: High AC in GnomAd4 at 244 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.391G>A	p.Glu131Lys	missense	Exon 4 of 12	NP_000368.1	P42768
	WAS	NM_001438877.1		c.391G>A	p.Glu131Lys	missense	Exon 4 of 12	NP_001425806.1
	WAS	NM_001438878.1		c.391G>A	p.Glu131Lys	missense	Exon 4 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.391G>A	p.Glu131Lys	missense	Exon 4 of 12	ENSP00000365891.4	P42768
	WAS	ENST00000698635.1		c.391G>A	p.Glu131Lys	missense	Exon 4 of 12	ENSP00000513850.1	A0A8V8TM35
	WAS	ENST00000698626.1		c.391G>A	p.Glu131Lys	missense	Exon 4 of 13	ENSP00000513845.1	A0A8V8TNH9

Frequencies

GnomAD3 genomes AF: 0.00216 AC: 243 AN: 112317 Hom.: 1 Cov.: 23

Gnomad AFR AF: 0.000291

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000942

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00146

Gnomad FIN AF: 0.00619

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00336

Gnomad OTH AF: 0.00199

GnomAD2 exomes AF: 0.00259 AC: 344 AN: 132777 AF XY: 0.00222

Gnomad AFR exome AF: 0.000226

Gnomad AMR exome AF: 0.000456

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00639

Gnomad NFE exome AF: 0.00384

Gnomad OTH exome AF: 0.00247

GnomAD4 exome AF: 0.00270 AC: 2883 AN: 1068409 Hom.: 4 Cov.: 33 AF XY: 0.00259 AC XY: 901 AN XY: 348391

African (AFR) AF: 0.000196 AC: 5 AN: 25493

American (AMR) AF: 0.000427 AC: 13 AN: 30455

Ashkenazi Jewish (ASJ) AF: 0.0000529 AC: 1 AN: 18921

East Asian (EAS) AF: 0.00 AC: 0 AN: 28312

South Asian (SAS) AF: 0.00268 AC: 137 AN: 51094

European-Finnish (FIN) AF: 0.00584 AC: 225 AN: 38553

Middle Eastern (MID) AF: 0.00414 AC: 17 AN: 4110

European-Non Finnish (NFE) AF: 0.00288 AC: 2377 AN: 826520

Other (OTH) AF: 0.00240 AC: 108 AN: 44951

GnomAD4 genome AF: 0.00217 AC: 244 AN: 112368 Hom.: 1 Cov.: 23 AF XY: 0.00223 AC XY: 77 AN XY: 34518

African (AFR) AF: 0.000291 AC: 9 AN: 30963

American (AMR) AF: 0.000941 AC: 10 AN: 10625

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2652

East Asian (EAS) AF: 0.00 AC: 0 AN: 3569

South Asian (SAS) AF: 0.00146 AC: 4 AN: 2733

European-Finnish (FIN) AF: 0.00619 AC: 38 AN: 6136

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 219

European-Non Finnish (NFE) AF: 0.00336 AC: 179 AN: 53264

Other (OTH) AF: 0.00262 AC: 4 AN: 1525

Alfa AF: 0.00248 Hom.: 113

Bravo AF: 0.00164

TwinsUK AF: 0.00378 AC: 14

ALSPAC AF: 0.00312 AC: 9

ESP6500AA AF: 0.000261 AC: 1

ESP6500EA AF: 0.00343 AC: 23

ExAC AF: 0.00254 AC: 296

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	Wiskott-Aldrich syndrome;C1839163:Thrombocytopenia 1;C1845987:X-linked severe congenital neutropenia (2)
-	1	-	Thrombocytopenia 1 (1)
-	-	1	WAS-related disorder (1)
-	-	1	Wiskott-Aldrich syndrome (1)
-	-	1	X-linked severe congenital neutropenia (1)
-	-	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.65
CADD	Benign	23
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.79	D
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.97	D
MetaRNN	Benign	0.0078	T
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.9	M
PhyloP100		1.6
PrimateAI	Uncertain	0.62	T
PROVEAN	Uncertain	-3.4	D
REVEL	Pathogenic	0.84
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.028	D
Polyphen		1.0	D
Vest4		0.065
MVP		1.0
MPC		1.6
ClinPred		0.033	T
GERP RS		4.3
Varity_R		0.56
gMVP		0.91
Mutation Taster		=68/32	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs146220228; hg19: chrX-48544153;