chrX-48683907-T-G

Variant names:

• chrX-48683907-T-G
• NM_000377.3:c.54T>G

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Strong BP6_Moderate BP7

The NM_000377.3(WAS):​c.54T>G​(p.Val18Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., 0 hem., cov: 22)
  • Exomes 𝑓: 0.00022 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: WAS NM_000377.3 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.440
• 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 -7 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant X-48683907-T-G is Benign according to our data. Variant chrX-48683907-T-G is described in ClinVar as Likely_benign. ClinVar VariationId is 2660463.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.44 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.54T>G	p.Val18Val	synonymous	Exon 1 of 12	NP_000368.1	P42768
	WAS	NM_001438877.1		c.54T>G	p.Val18Val	synonymous	Exon 1 of 12	NP_001425806.1
	WAS	NM_001438878.1		c.54T>G	p.Val18Val	synonymous	Exon 1 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.54T>G	p.Val18Val	synonymous	Exon 1 of 12	ENSP00000365891.4	P42768
	WAS	ENST00000698635.1		c.54T>G	p.Val18Val	synonymous	Exon 1 of 12	ENSP00000513850.1	A0A8V8TM35
	WAS	ENST00000698626.1		c.54T>G	p.Val18Val	synonymous	Exon 1 of 13	ENSP00000513845.1	A0A8V8TNH9

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 111294 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.00

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

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000222 AC: 242 AN: 1091112 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 360918

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

African (AFR) AF: 0.0000761 AC: 2 AN: 26275

American (AMR) AF: 0.0000284 AC: 1 AN: 35202

Ashkenazi Jewish (ASJ) AF: 0.000155 AC: 3 AN: 19341

East Asian (EAS) AF: 0.00 AC: 0 AN: 30168

South Asian (SAS) AF: 0.0000185 AC: 1 AN: 54002

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40528

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4124

European-Non Finnish (NFE) AF: 0.000274 AC: 229 AN: 835626

Other (OTH) AF: 0.000131 AC: 6 AN: 45846

⚠️ 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: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 111346 Hom.: 0 Cov.: 22 AF XY: 0.00 AC XY: 0 AN XY: 33536

African (AFR) AF: 0.00 AC: 0 AN: 30671

American (AMR) AF: 0.00 AC: 0 AN: 10473

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2648

East Asian (EAS) AF: 0.00 AC: 0 AN: 3508

South Asian (SAS) AF: 0.00 AC: 0 AN: 2657

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6031

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 217

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 52946

Other (OTH) AF: 0.00 AC: 0 AN: 1515

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	4.6
DANN	Benign	0.59
PhyloP100		0.44
PromoterAI		0.017	Neutral

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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

hg19: chrX-48542296;