17-7347104-G-T

Position:

• chr17-7347104-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_014716.4(ACAP1):​c.1205G>T​(p.Gly402Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: ACAP1 NM_014716.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.37

Genes affected

ACAP1 (HGNC:16467): (ArfGAP with coiled-coil, ankyrin repeat and PH domains 1) Predicted to enable GTPase activator activity and metal ion binding activity. Predicted to be involved in protein transport and regulation of catalytic activity. Located in membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ACAP1	NM_014716.4	c.1205G>T	p.Gly402Val	missense_variant	14/22	ENST00000158762.8	NP_055531.1
ACAP1	XM_047437150.1	c.983G>T	p.Gly328Val	missense_variant	14/22		XP_047293106.1
ACAP1	XM_047437151.1	c.983G>T	p.Gly328Val	missense_variant	13/21		XP_047293107.1
ACAP1	XM_047437152.1	c.1205G>T	p.Gly402Val	missense_variant	14/18		XP_047293108.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ACAP1	ENST00000158762.8	c.1205G>T	p.Gly402Val	missense_variant	14/22	1	NM_014716.4	ENSP00000158762	P1
ACAP1	ENST00000570439.1	n.1774G>T		non_coding_transcript_exon_variant	1/1
ACAP1	ENST00000576594.1			upstream_gene_variant		2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 15, 2024

The c.1205G>T (p.G402V) alteration is located in exon 14 (coding exon 14) of the ACAP1 gene. This alteration results from a G to T substitution at nucleotide position 1205, causing the glycine (G) at amino acid position 402 to be replaced by a valine (V). 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	Benign	0.085
BayesDel_addAF	Uncertain	0.012	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.034	T
Eigen	Benign	-0.17
Eigen_PC	Benign	-0.018
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.75	T
M_CAP	Benign	0.030	D
MetaRNN	Uncertain	0.44	T
MetaSVM	Benign	-0.81	T
MutationAssessor	Benign	0.0	N
MutationTaster	Benign	1.0	D
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.75	N
REVEL	Benign	0.22
Sift	Benign	0.062	T
Sift4G	Benign	0.22	T
Polyphen		0.36	B
Vest4		0.60
MutPred		0.28		Loss of disorder (P = 0.0468);
MVP		0.70
MPC		0.89
ClinPred		0.26	T
GERP RS		4.8
Varity_R		0.16
gMVP		0.47

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

LitVar

Other links and lift over

dbSNP: rs140256517; hg19: chr17-7250423;