6-138253955-C-A

Position:

• chr6-138253955-C-A

Variant summary

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

The ENST00000251691.5(ARFGEF3):​c.741C>A​(p.His247Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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)
• Consequence: ARFGEF3 ENST00000251691.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.42

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15050021).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ARFGEF3	NM_020340.5	c.741C>A	p.His247Gln	missense_variant	9/34	ENST00000251691.5	NP_065073.3
ARFGEF3	XM_047419108.1	c.246C>A	p.His82Gln	missense_variant	6/31		XP_047275064.1
ARFGEF3	XR_001743524.2	n.889C>A		non_coding_transcript_exon_variant	9/35

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ARFGEF3	ENST00000251691.5	c.741C>A	p.His247Gln	missense_variant	9/34	1	NM_020340.5	ENSP00000251691	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

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

Jul 26, 2022

The c.741C>A (p.H247Q) alteration is located in exon 9 (coding exon 9) of the ARFGEF3 gene. This alteration results from a C to A substitution at nucleotide position 741, causing the histidine (H) at amino acid position 247 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	Benign	0.17
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	15
DANN	Benign	0.93
DEOGEN2	Benign	0.085	T
Eigen	Benign	-0.47
Eigen_PC	Benign	-0.42
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.55	T
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.15	T
MetaSVM	Benign	-0.85	T
MutationAssessor	Benign	1.7	L
MutationTaster	Benign	0.97	D
PrimateAI	Benign	0.41	T
PROVEAN	Uncertain	-2.8	D
REVEL	Benign	0.088
Sift	Benign	0.23	T
Sift4G	Pathogenic	0.0	D
Polyphen		0.44	B
Vest4		0.15
MutPred		0.25		Gain of relative solvent accessibility (P = 0.09);
MVP		0.093
MPC		0.28
ClinPred		0.60	D
GERP RS		-0.76
Varity_R		0.14
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

No publications associated with this variant yet.

Other links and lift over

hg19: chr6-138575092;