chrX-48688919-G-C

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP7

The NM_000377.3(WAS):​c.1191G>C​(p.Pro397Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. P397P) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 0.0 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: WAS NM_000377.3 synonymous
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• 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: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.04).
• BP7: Synonymous conserved (PhyloP=-2.66 with no splicing effect.

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>C	p.Pro397Pro	synonymous	Exon 10 of 12	NP_000368.1	P42768
	WAS	NM_001438877.1		c.1191G>C	p.Pro397Pro	synonymous	Exon 10 of 12	NP_001425806.1
	WAS	NM_001438878.1		c.1035G>C	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>C	p.Pro397Pro	synonymous	Exon 10 of 12	ENSP00000365891.4	P42768
	WAS	ENST00000698635.1		c.1191G>C	p.Pro397Pro	synonymous	Exon 10 of 12	ENSP00000513850.1	A0A8V8TM35
	WAS	ENST00000698626.1		c.1191G>C	p.Pro397Pro	synonymous	Exon 10 of 13	ENSP00000513845.1	A0A8V8TNH9

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 922079 Hom.: 0 Cov.: 35 AF XY: 0.00 AC XY: 0 AN XY: 289761

African (AFR) AF: 0.00 AC: 0 AN: 21394

American (AMR) AF: 0.00 AC: 0 AN: 24124

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 13318

East Asian (EAS) AF: 0.00 AC: 0 AN: 18227

South Asian (SAS) AF: 0.00 AC: 0 AN: 45709

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 24473

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 736553

Other (OTH) AF: 0.00 AC: 0 AN: 35675

GnomAD4 genome Cov.: 22

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.014
DANN	Benign	0.36
PhyloP100		-2.7

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;