17-7343408-G-T

Variant summary

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

The NM_014716.4(ACAP1):c.374G>T(p.Arg125Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: ACAP1 NM_014716.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.20

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	UniProt
ACAP1	NM_014716.4	c.374G>T	p.Arg125Leu	missense_variant	6/22	ENST00000158762.8
ACAP1	XM_047437150.1	c.152G>T	p.Arg51Leu	missense_variant	6/22
ACAP1	XM_047437151.1	c.152G>T	p.Arg51Leu	missense_variant	5/21
ACAP1	XM_047437152.1	c.374G>T	p.Arg125Leu	missense_variant	6/18

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACAP1	ENST00000158762.8	c.374G>T	p.Arg125Leu	missense_variant	6/22	1	NM_014716.4	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 31

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

Feb 10, 2022

The c.374G>T (p.R125L) alteration is located in exon 6 (coding exon 6) of the ACAP1 gene. This alteration results from a G to T substitution at nucleotide position 374, causing the arginine (R) at amino acid position 125 to be replaced by a leucine (L). 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	Uncertain	0.42
BayesDel_addAF	Benign	-0.011	T
BayesDel_noAF	Benign	-0.25
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Benign	0.22	T;.;T
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.84	T;T;T
M_CAP	Benign	0.023	T
MetaRNN	Uncertain	0.48	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.7	L;.;.
MutationTaster	Benign	0.80	D
PrimateAI	Uncertain	0.72	T
PROVEAN	Uncertain	-3.8	D;.;.
REVEL	Benign	0.19
Sift	Uncertain	0.022	D;.;.
Sift4G	Uncertain	0.051	T;D;D
Polyphen		0.96	D;.;.
Vest4		0.57
MutPred		0.41		Loss of MoRF binding (P = 0.0213);.;.;
MVP		0.66
MPC		1.2
ClinPred		0.98	D
GERP RS		4.2
Varity_R		0.58
gMVP		0.35

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: rs746768465; hg19: chr17-7246727; COSMIC: COSV104549471; COSMIC: COSV104549471;