1-1294464-C-T

Variant names:

• chr1-1294464-C-T
• rs867514004
• NM_030649.3:c.2077G>A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_030649.3(ACAP3):​c.2077G>A​(p.Glu693Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00000425 in 1,411,198 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000043 (0 hom.)
• Consequence: ACAP3 NM_030649.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.89

Genes affected

ACAP3 (HGNC:16754): (ArfGAP with coiled-coil, ankyrin repeat and PH domains 3) Predicted to enable GTPase activator activity and metal ion binding activity. Predicted to be involved in regulation of catalytic activity. Predicted to act upstream of or within neuron migration and regulation of neuron projection development. Predicted to be located in growth cone. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.35454553).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACAP3	NM_030649.3	c.2077G>A	p.Glu693Lys	missense_variant	Exon 21 of 24	ENST00000354700.10	NP_085152.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACAP3	ENST00000354700.10	c.2077G>A	p.Glu693Lys	missense_variant	Exon 21 of 24	1	NM_030649.3	ENSP00000346733.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000425 AC: 6 AN: 1411198 Hom.: 0 Cov.: 32 AF XY: 0.00000715 AC XY: 5 AN XY: 699780

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000549

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 02, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2077G>A (p.E693K) alteration is located in exon 21 (coding exon 21) of the ACAP3 gene. This alteration results from a G to A substitution at nucleotide position 2077, causing the glutamic acid (E) at amino acid position 693 to be replaced by a lysine (K). 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	0.19
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.50
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.17	T;.
Eigen	Benign	-0.063
Eigen_PC	Benign	0.072
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.93	D;D
M_CAP	Benign	0.055	D
MetaRNN	Benign	0.35	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.29	N;.
PrimateAI	Pathogenic	0.88	D
PROVEAN	Uncertain	-2.7	D;D
REVEL	Benign	0.17
Sift	Benign	0.080	T;T
Sift4G	Benign	0.062	T;T
Polyphen		0.92	P;B
Vest4		0.56
MutPred		0.74		Gain of ubiquitination at E693 (P = 0.0219);.;
MVP		0.31
MPC		0.66
ClinPred		0.81	D
GERP RS		4.5
Varity_R		0.29
gMVP		0.25

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs867514004; hg19: chr1-1229844; COSMIC: COSV57642853; COSMIC: COSV57642853;