1-1294522-G-C

Position:

• chr1-1294522-G-C

Variant summary

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

The NM_030649.3(ACAP3):​c.2019C>G​(p.His673Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000074 in 1,350,592 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 7.4e-7 (0 hom.)
• Consequence: ACAP3 NM_030649.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.40

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]

ACAP3 (HGNC:):

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, 0.761

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ACAP3	NM_030649.3	c.2019C>G	p.His673Gln	missense_variant	21/24	ENST00000354700.10	NP_085152.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ACAP3	ENST00000354700.10	c.2019C>G	p.His673Gln	missense_variant	21/24	1	NM_030649.3	ENSP00000346733.5

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 7.40e-7 AC: 1 AN: 1350592 Hom.: 0 Cov.: 32 AF XY: 0.00000150 AC XY: 1 AN XY: 666774

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: 9.37e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

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 12, 2023

The c.2019C>G (p.H673Q) alteration is located in exon 21 (coding exon 21) of the ACAP3 gene. This alteration results from a C to G substitution at nucleotide position 2019, causing the histidine (H) at amino acid position 673 to be replaced by a glutamine (Q). 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	0.56
BayesDel_addAF	Benign	0.0054	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	21
DANN	Benign	0.97
DEOGEN2	Benign	0.23	T;.
Eigen	Benign	-0.045
Eigen_PC	Benign	-0.18
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.71	T;T
M_CAP	Pathogenic	0.72	D
MetaRNN	Pathogenic	0.76	D;D
MetaSVM	Benign	-0.58	T
MutationAssessor	Benign	1.6	L;.
PrimateAI	Pathogenic	0.86	D
PROVEAN	Uncertain	-3.0	D;D
REVEL	Uncertain	0.33
Sift	Uncertain	0.0050	D;T
Sift4G	Uncertain	0.0070	D;D
Polyphen		0.87	P;P
Vest4		0.51
MutPred		0.48		Loss of helix (P = 0.0104);.;
MVP		0.67
MPC		0.89
ClinPred		0.94	D
GERP RS		2.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.16
gMVP		0.47

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: chr1-1229902;