NM_003931.3:c.-127+2568A>G

Variant names:

• chr6-110176030-T-C
• rs4945851
• NM_003931.3:c.-127+2568A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_003931.3(WASF1):​c.-127+2568A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.279 in 151,920 control chromosomes in the GnomAD database, including 8,539 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.28 (8539 hom., cov: 32)
• Consequence: WASF1 NM_003931.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.752
• Publications: 4 publications found

Genes affected

WASF1 (HGNC:12732): (WASP family member 1) The protein encoded by this gene, a member of the Wiskott-Aldrich syndrome protein (WASP)-family, plays a critical role downstream of Rac, a Rho-family small GTPase, in regulating the actin cytoskeleton required for membrane ruffling. It has been shown to associate with an actin nucleation core Arp2/3 complex while enhancing actin polymerization in vitro. Wiskott-Aldrich syndrome is a disease of the immune system, likely due to defects in regulation of actin cytoskeleton. Multiple alternatively spliced transcript variants encoding the same protein have been found for this gene. [provided by RefSeq, Jul 2008]

WASF1 Gene-Disease associations (from GenCC):

• neurodevelopmental disorder with absent language and variable seizures

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
• neurodevelopmental disorder

  Inheritance: AD Classification: LIMITED Submitted by: G2P

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.568 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003931.3. 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
	WASF1	NM_003931.3	MANE Select	c.-127+2568A>G		intron	N/A	NP_003922.1
	WASF1	NM_001024934.2		c.-29+2568A>G		intron	N/A	NP_001020105.1
	WASF1	NM_001024935.2		c.-127+3409A>G		intron	N/A	NP_001020106.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WASF1	ENST00000392589.6	TSL:5 MANE Select	c.-127+2568A>G		intron	N/A	ENSP00000376368.1
	WASF1	ENST00000359451.6	TSL:1	c.-127+3409A>G		intron	N/A	ENSP00000352425.2
	WASF1	ENST00000392587.6	TSL:1	c.-29+3409A>G		intron	N/A	ENSP00000376366.2

Frequencies

GnomAD3 genomes AF: 0.278 AC: 42253 AN: 151802 Hom.: 8505 Cov.: 32

Gnomad AFR AF: 0.574

Gnomad AMI AF: 0.300

Gnomad AMR AF: 0.204

Gnomad ASJ AF: 0.129

Gnomad EAS AF: 0.222

Gnomad SAS AF: 0.279

Gnomad FIN AF: 0.149

Gnomad MID AF: 0.139

Gnomad NFE AF: 0.149

Gnomad OTH AF: 0.225

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.279 AC: 42354 AN: 151920 Hom.: 8539 Cov.: 32 AF XY: 0.278 AC XY: 20628 AN XY: 74256

African (AFR) AF: 0.574 AC: 23775 AN: 41400

American (AMR) AF: 0.205 AC: 3124 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.129 AC: 448 AN: 3468

East Asian (EAS) AF: 0.222 AC: 1150 AN: 5178

South Asian (SAS) AF: 0.279 AC: 1341 AN: 4814

European-Finnish (FIN) AF: 0.149 AC: 1576 AN: 10558

Middle Eastern (MID) AF: 0.139 AC: 41 AN: 294

European-Non Finnish (NFE) AF: 0.149 AC: 10148 AN: 67910

Other (OTH) AF: 0.226 AC: 478 AN: 2112

Alfa AF: 0.190 Hom.: 1633

Bravo AF: 0.295

Asia WGS AF: 0.275 AC: 956 AN: 3472

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.38
DANN	Benign	0.66
PhyloP100		-0.75
Mutation Taster		=100/0	polymorphism (auto)

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

dbSNP: rs4945851; hg19: chr6-110497233; COSMIC: COSV55618957; COSMIC: COSV55618957;