rs774254232

Variant names:

• chr19-45521361-C-A
• rs774254232
• NM_003370.4:c.383C>A

Your query was ambiguous. Multiple possible variants found:

• chr19-45521361-C-A
• chr19-45521361-C-G
• chr19-45521361-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_003370.4(VASP):​c.383C>A​(p.Ser128*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000007 in 1,429,044 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: VASP NM_003370.4 stop_gained
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.31
• Publications: 0 publications found

Genes affected

VASP (HGNC:12652): (vasodilator stimulated phosphoprotein) Vasodilator-stimulated phosphoprotein (VASP) is a member of the Ena-VASP protein family. Ena-VASP family members contain an EHV1 N-terminal domain that binds proteins containing E/DFPPPPXD/E motifs and targets Ena-VASP proteins to focal adhesions. In the mid-region of the protein, family members have a proline-rich domain that binds SH3 and WW domain-containing proteins. Their C-terminal EVH2 domain mediates tetramerization and binds both G and F actin. VASP is associated with filamentous actin formation and likely plays a widespread role in cell adhesion and motility. VASP may also be involved in the intracellular signaling pathways that regulate integrin-extracellular matrix interactions. VASP is regulated by the cyclic nucleotide-dependent kinases PKA and PKG. [provided by RefSeq, Jul 2008]

LOC107985315 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003370.4. 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
	VASP	NM_003370.4	MANE Select	c.383C>A	p.Ser128*	stop_gained	Exon 4 of 13	NP_003361.1	A0A024R0V4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VASP	ENST00000245932.11	TSL:1 MANE Select	c.383C>A	p.Ser128*	stop_gained	Exon 4 of 13	ENSP00000245932.5	P50552
	VASP	ENST00000916562.1		c.476C>A	p.Ser159*	stop_gained	Exon 4 of 13	ENSP00000586621.1
	VASP	ENST00000862928.1		c.383C>A	p.Ser128*	stop_gained	Exon 4 of 13	ENSP00000532987.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.00e-7 AC: 1 AN: 1429044 Hom.: 0 Cov.: 31 AF XY: 0.00000141 AC XY: 1 AN XY: 707860

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

African (AFR) AF: 0.00 AC: 0 AN: 32996

American (AMR) AF: 0.00 AC: 0 AN: 39602

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25350

East Asian (EAS) AF: 0.00 AC: 0 AN: 38296

South Asian (SAS) AF: 0.0000123 AC: 1 AN: 81522

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51270

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5192

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1095740

Other (OTH) AF: 0.00 AC: 0 AN: 59076

⚠️ 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 Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.45
CADD	Pathogenic	44
DANN	Uncertain	0.99
Eigen	Uncertain	0.34
Eigen_PC	Benign	0.063
FATHMM_MKL	Benign	0.65	D
PhyloP100		2.3
Vest4		0.67
GERP RS		3.2
Mutation Taster		=22/178	disease causing (fs/PTC)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.73		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.73		Position offset: -3

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs774254232; hg19: chr19-46024619;