6-138210014-C-A

Position:

• chr6-138210014-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_020340.5(ARFGEF3):​c.324C>A​(p.Asn108Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,496 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ARFGEF3 NM_020340.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.603

Genes affected

ARFGEF3 (HGNC:21213): (ARFGEF family member 3) Predicted to enable guanyl-nucleotide exchange factor activity. Predicted to be involved in actin cytoskeleton organization. Predicted to be located in transport vesicle membrane. Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

ARFGEF3 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08808306).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ARFGEF3	NM_020340.5	c.324C>A	p.Asn108Lys	missense_variant	4/34	ENST00000251691.5	NP_065073.3
ARFGEF3	XR_001743524.2	n.472C>A		non_coding_transcript_exon_variant	4/35

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ARFGEF3	ENST00000251691.5	c.324C>A	p.Asn108Lys	missense_variant	4/34	1	NM_020340.5	ENSP00000251691.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461496 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 727036

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

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

Apr 07, 2023

The c.324C>A (p.N108K) alteration is located in exon 4 (coding exon 4) of the ARFGEF3 gene. This alteration results from a C to A substitution at nucleotide position 324, causing the asparagine (N) at amino acid position 108 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	Pathogenic	0.56
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	3.6
DANN	Benign	0.95
DEOGEN2	Benign	0.061	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.17	N
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.0039	T
MetaRNN	Benign	0.088	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.7	L
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.024
Sift	Benign	0.063	T
Sift4G	Uncertain	0.046	D
Polyphen		0.36	B
Vest4		0.35
MutPred		0.41		Gain of ubiquitination at N108 (P = 0.0162);
MVP		0.12
MPC		0.34
ClinPred		0.46	T
GERP RS		-5.9
Varity_R		0.077
gMVP		0.27

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: rs115941727; hg19: chr6-138531151;