chr22-42857143-T-G

Variant names:

• chr22-42857143-T-G
• NM_014570.5:c.40A>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_014570.5(ARFGAP3):​c.40A>C​(p.Lys14Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000022 in 1,362,940 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000022 (0 hom.)
• Consequence: ARFGAP3 NM_014570.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.80
• Publications: 0 publications found

Genes affected

ARFGAP3 (HGNC:661): (ADP ribosylation factor GTPase activating protein 3) The protein encoded by this gene is a GTPase-activating protein (GAP) that associates with the Golgi apparatus and regulates the early secretory pathway of proteins. The encoded protein promotes hydrolysis of ADP-ribosylation factor 1 (ARF1)-bound GTP, which is required for the dissociation of coat proteins from Golgi-derived membranes and vesicles. Dissociation of the coat proteins is a prerequisite for the fusion of these vesicles with target compartments. The activity of this protein is sensitive to phospholipids. Multiple transcript variants encoding different isoforms have been found for this gene. This gene was originally known as ARFGAP1, but that is now the name of a related but different gene. [provided by RefSeq, Nov 2008]

ENSG00000307798 (HGNC:):

PACSIN2 (HGNC:8571): (protein kinase C and casein kinase substrate in neurons 2) This gene is a member of the protein kinase C and casein kinase substrate in neurons family. The encoded protein is involved in linking the actin cytoskeleton with vesicle formation by regulating tubulin polymerization. Alternative splicing results in multiple transcript variants. [provided by RefSeq, May 2010]

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.33574086).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014570.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARFGAP3	NM_014570.5	MANE Select	c.40A>C	p.Lys14Gln	missense	Exon 1 of 16	NP_055385.3
	ARFGAP3	NM_001142293.2		c.40A>C	p.Lys14Gln	missense	Exon 1 of 15	NP_001135765.1	Q9NP61-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARFGAP3	ENST00000263245.10	TSL:1 MANE Select	c.40A>C	p.Lys14Gln	missense	Exon 1 of 16	ENSP00000263245.5	Q9NP61-1
	ARFGAP3	ENST00000437119.6	TSL:1	c.40A>C	p.Lys14Gln	missense	Exon 1 of 15	ENSP00000388791.2	Q9NP61-2
	ARFGAP3	ENST00000938504.1		c.40A>C	p.Lys14Gln	missense	Exon 1 of 15	ENSP00000608563.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000220 AC: 3 AN: 1362940 Hom.: 0 Cov.: 30 AF XY: 0.00000297 AC XY: 2 AN XY: 672514

African (AFR) AF: 0.00 AC: 0 AN: 28044

American (AMR) AF: 0.00 AC: 0 AN: 32044

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24016

East Asian (EAS) AF: 0.00 AC: 0 AN: 31034

South Asian (SAS) AF: 0.0000131 AC: 1 AN: 76116

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48242

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5570

European-Non Finnish (NFE) AF: 0.00000188 AC: 2 AN: 1061648

Other (OTH) AF: 0.00 AC: 0 AN: 56226

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
CADD	Pathogenic	26
DANN	Uncertain	0.98
DEOGEN2	Benign	0.064	T
Eigen	Benign	0.12
Eigen_PC	Benign	0.21
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.95	D
M_CAP	Uncertain	0.23	D
MetaRNN	Benign	0.34	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.6	L
PhyloP100		4.8
PrimateAI	Pathogenic	0.87	D
PROVEAN	Uncertain	-3.0	D
REVEL	Benign	0.10
Sift	Benign	0.055	T
Sift4G	Benign	0.065	T
Polyphen		0.17	B
Vest4		0.24
MutPred		0.47		Loss of methylation at K14 (P = 0.0367)
MVP		0.48
MPC		0.27
ClinPred		0.98	D
GERP RS		4.0
PromoterAI		0.0090	Neutral
Varity_R		0.48
gMVP		0.50
Mutation Taster		=66/34	polymorphism

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

Other links and lift over

hg19: chr22-43253149;