19-45522493-C-T

Variant names:

• chr19-45522493-C-T
• rs776884448
• NM_003370.4:c.632C>T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_003370.4(VASP):​c.632C>T​(p.Pro211Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000137 in 1,467,306 control chromosomes in the GnomAD database, including 1 homozygotes. 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. P211P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00013 (1 hom.)
• Consequence: VASP NM_003370.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.37
• 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: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.022669733).
• BS2: High AC in GnomAd4 at 25 AD gene.

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.632C>T	p.Pro211Leu	missense	Exon 6 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.632C>T	p.Pro211Leu	missense	Exon 6 of 13	ENSP00000245932.5	P50552
	VASP	ENST00000916562.1		c.725C>T	p.Pro242Leu	missense	Exon 6 of 13	ENSP00000586621.1
	VASP	ENST00000862928.1		c.659C>T	p.Pro220Leu	missense	Exon 6 of 13	ENSP00000532987.1

Frequencies

GnomAD3 genomes AF: 0.000164 AC: 25 AN: 152146 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000782 AC: 6 AN: 76702 AF XY: 0.0000766

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000815

Gnomad ASJ exome AF: 0.00202

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000331

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000134 AC: 176 AN: 1315160 Hom.: 1 Cov.: 34 AF XY: 0.000147 AC XY: 94 AN XY: 641570

African (AFR) AF: 0.0000347 AC: 1 AN: 28808

American (AMR) AF: 0.0000902 AC: 2 AN: 22162

Ashkenazi Jewish (ASJ) AF: 0.00519 AC: 100 AN: 19274

East Asian (EAS) AF: 0.00 AC: 0 AN: 35392

South Asian (SAS) AF: 0.0000154 AC: 1 AN: 65130

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40994

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3986

European-Non Finnish (NFE) AF: 0.0000517 AC: 54 AN: 1045058

Other (OTH) AF: 0.000331 AC: 18 AN: 54356

GnomAD4 genome AF: 0.000164 AC: 25 AN: 152146 Hom.: 0 Cov.: 32 AF XY: 0.000202 AC XY: 15 AN XY: 74332

African (AFR) AF: 0.0000241 AC: 1 AN: 41440

American (AMR) AF: 0.0000654 AC: 1 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00576 AC: 20 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 67984

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.000485 Hom.: 2

Bravo AF: 0.000155

ExAC AF: 0.000121 AC: 12

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
AlphaMissense	Uncertain	0.39
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.22
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Pathogenic	0.82	D
Eigen	Benign	0.034
Eigen_PC	Benign	0.094
FATHMM_MKL	Benign	0.73	D
LIST_S2	Benign	0.81	T
M_CAP	Uncertain	0.16	D
MetaRNN	Benign	0.023	T
MetaSVM	Benign	-0.44	T
MutationAssessor	Pathogenic	3.3	M
PhyloP100		3.4
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-5.5	D
REVEL	Uncertain	0.30
Sift	Benign	0.12	T
Sift4G	Uncertain	0.022	D
Polyphen		0.24	B
Vest4		0.39
MutPred		0.22		Gain of helix (P = 0.0164)
MVP		0.56
MPC		0.35
ClinPred		0.84	D
GERP RS		3.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.30
gMVP		0.34
Mutation Taster		=81/19	polymorphism

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: rs776884448; hg19: chr19-46025751;