17-7346872-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_014716.4(ACAP1):c.1072A>T(p.Ser358Cys) 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: 33)
• Consequence: ACAP1 NM_014716.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.87

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 4 ACMG points.

• PM1: In a mutagenesis_site No effect on interaction with ITGB1. (size 0) in uniprot entity ACAP1_HUMAN
• 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.1072A>T	p.Ser358Cys	missense_variant	13/22	ENST00000158762.8
ACAP1	XM_047437150.1	c.850A>T	p.Ser284Cys	missense_variant	13/22
ACAP1	XM_047437151.1	c.850A>T	p.Ser284Cys	missense_variant	12/21
ACAP1	XM_047437152.1	c.1072A>T	p.Ser358Cys	missense_variant	13/18

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACAP1	ENST00000158762.8	c.1072A>T	p.Ser358Cys	missense_variant	13/22	1	NM_014716.4	P1
ACAP1	ENST00000570439.1	n.1542A>T		non_coding_transcript_exon_variant	1/1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

Bravo AF: 0.0000113

ExAC AF: 0.00000824 AC: 1

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

Dec 26, 2023

The c.1072A>T (p.S358C) alteration is located in exon 13 (coding exon 13) of the ACAP1 gene. This alteration results from a A to T substitution at nucleotide position 1072, causing the serine (S) at amino acid position 358 to be replaced by a cysteine (C). 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	0.20
BayesDel_addAF	Uncertain	0.064	T
BayesDel_noAF	Benign	-0.15
Cadd	Uncertain	25
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.51	D
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Benign	0.077	D
MetaRNN	Uncertain	0.69	D
MetaSVM	Benign	-0.29	T
MutationAssessor	Benign	1.9	L
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.70	T
PROVEAN	Uncertain	-3.6	D
REVEL	Uncertain	0.64
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.035	D
Polyphen		0.92	P
Vest4		0.60
MutPred		0.63		Loss of disorder (P = 0.0041);
MVP		0.83
MPC		1.3
ClinPred		0.99	D
GERP RS		4.6
Varity_R		0.79
gMVP		0.73

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs756756826; hg19: chr17-7250191;