17-30949294-T-A

Variant names:

• chr17-30949294-T-A
• NM_018404.3:c.665T>A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_018404.3(ADAP2):​c.665T>A​(p.Val222Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: ADAP2 NM_018404.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.01

Genes affected

ADAP2 (HGNC:16487): (ArfGAP with dual PH domains 2) The protein encoded by this gene binds beta-tubulin and increases the stability of microtubules. The encoded protein can also translocate to the cell membrane and bind phosphatidylinositol 3,4,5-trisphosphate (PtdInsP3) and inositol 1,3,4,5-tetrakisphosphate (InsP4). In addition, this protein is a GTPase-activating protein for ADP ribosylation factor 6 and may be able to block the entry of some RNA viruses. [provided by RefSeq, Oct 2016]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.839

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADAP2	NM_018404.3	c.665T>A	p.Val222Glu	missense_variant	Exon 7 of 11	ENST00000330889.8	NP_060874.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADAP2	ENST00000330889.8	c.665T>A	p.Val222Glu	missense_variant	Exon 7 of 11	1	NM_018404.3	ENSP00000329468.3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 12, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.665T>A (p.V222E) alteration is located in exon 7 (coding exon 7) of the ADAP2 gene. This alteration results from a T to A substitution at nucleotide position 665, causing the valine (V) at amino acid position 222 to be replaced by a glutamic acid (E). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.29
CADD	Pathogenic	30
DANN	Benign	0.92
DEOGEN2	Uncertain	0.51	D;.;T;T
Eigen	Pathogenic	0.70
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D;D;D;D
M_CAP	Uncertain	0.17	D
MetaRNN	Pathogenic	0.84	D;D;D;D
MetaSVM	Benign	-0.99	T
MutationAssessor	Uncertain	2.5	M;.;.;.
PrimateAI	Pathogenic	0.80	T
PROVEAN	Pathogenic	-5.5	D;.;.;.
REVEL	Uncertain	0.61
Sift	Uncertain	0.0020	D;.;.;.
Sift4G	Uncertain	0.015	D;D;D;D
Polyphen		1.0	D;.;D;.
Vest4		0.90
MutPred		0.61		.;.;Gain of disorder (P = 0.0126);.;
MVP		0.90
MPC		1.5
ClinPred		1.0	D
GERP RS		5.1
Varity_R		0.88
gMVP		0.79

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-29276312;