chr6-138253962-A-T

Position:

• chr6-138253962-A-T

Variant summary

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

The ENST00000251691.5(ARFGEF3):​c.748A>T​(p.Arg250Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000694 in 1,441,062 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: ARFGEF3 ENST00000251691.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.98

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ARFGEF3	NM_020340.5	c.748A>T	p.Arg250Trp	missense_variant	9/34	ENST00000251691.5	NP_065073.3
ARFGEF3	XM_047419108.1	c.253A>T	p.Arg85Trp	missense_variant	6/31		XP_047275064.1
ARFGEF3	XR_001743524.2	n.896A>T		non_coding_transcript_exon_variant	9/35

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ARFGEF3	ENST00000251691.5	c.748A>T	p.Arg250Trp	missense_variant	9/34	1	NM_020340.5	ENSP00000251691	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.94e-7 AC: 1 AN: 1441062 Hom.: 0 Cov.: 30 AF XY: 0.00000140 AC XY: 1 AN XY: 714896

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: 9.07e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

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

Nov 22, 2022

The c.748A>T (p.R250W) alteration is located in exon 9 (coding exon 9) of the ARFGEF3 gene. This alteration results from a A to T substitution at nucleotide position 748, causing the arginine (R) at amino acid position 250 to be replaced by a tryptophan (W). 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	0.18
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.26	T
Eigen	Benign	0.022
Eigen_PC	Benign	-0.023
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.017	T
MetaRNN	Uncertain	0.47	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.90	L
MutationTaster	Benign	0.89	D
PrimateAI	Uncertain	0.57	T
PROVEAN	Uncertain	-3.4	D
REVEL	Benign	0.10
Sift	Uncertain	0.017	D
Sift4G	Uncertain	0.0020	D
Polyphen		0.91	P
Vest4		0.51
MutPred		0.41		Loss of disorder (P = 0.0171);
MVP		0.14
MPC		0.62
ClinPred		0.82	D
GERP RS		-0.60
Varity_R		0.12
gMVP		0.36

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: rs1457229732; hg19: chr6-138575099;