8-67343251-T-A

Position:

• chr8-67343251-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The ENST00000262215.8(ARFGEF1):​c.37A>T​(p.Thr13Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T13I) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: ARFGEF1 ENST00000262215.8 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 5.80

Genes affected

ARFGEF1 (HGNC:15772): (ADP ribosylation factor guanine nucleotide exchange factor 1) ADP-ribosylation factors (ARFs) play an important role in intracellular vesicular trafficking. The protein encoded by this gene is involved in the activation of ARFs by accelerating replacement of bound GDP with GTP. It contains a Sec7 domain, which may be responsible for guanine-nucleotide exchange activity and also brefeldin A inhibition. [provided by RefSeq, Aug 2011]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), ARFGEF1. . Gene score misZ 5.3687 (greater than the threshold 3.09). Trascript score misZ 6.9454 (greater than threshold 3.09). GenCC has associacion of gene with developmental delay, impaired speech, and behavioral abnormalities, with or without seizures, schizophrenia.
• BP4: Computational evidence support a benign effect (MetaRNN=0.12152606).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ARFGEF1	NM_006421.5	c.37A>T	p.Thr13Ser	missense_variant	1/39	ENST00000262215.8	NP_006412.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ARFGEF1	ENST00000262215.8	c.37A>T	p.Thr13Ser	missense_variant	1/39	1	NM_006421.5	ENSP00000262215	P1
ARFGEF1	ENST00000519436.1	c.37A>T	p.Thr13Ser	missense_variant	2/5	3		ENSP00000429002

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 48

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

ARFGEF1-related disorder Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 13, 2023

The ARFGEF1 c.37A>T variant is predicted to result in the amino acid substitution p.Thr13Ser. To our knowledge, this variant has not been reported in the literature or in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	21
DANN	Benign	0.94
DEOGEN2	Benign	0.13	T;.
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.080
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.85	T;T
M_CAP	Uncertain	0.24	D
MetaRNN	Benign	0.12	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.73	N;.
MutationTaster	Benign	0.99	D
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	-1.1	N;N
REVEL	Benign	0.062
Sift	Benign	0.92	T;T
Sift4G	Benign	0.94	T;T
Polyphen		0.0020	B;.
Vest4		0.33
MutPred		0.23		Gain of disorder (P = 0.0696);Gain of disorder (P = 0.0696);
MVP		0.24
MPC		0.32
ClinPred		0.55	D
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.50
gMVP		0.21

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: chr8-68255486;