7-127591043-C-A

Position:

• chr7-127591043-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The ENST00000000233.10(ARF5):​c.411C>A​(p.Ser137Arg) 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. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: ARF5 ENST00000000233.10 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.290

Genes affected

ARF5 (HGNC:658): (ADP ribosylation factor 5) This gene is a member of the human ADP-ribosylation factor (ARF) gene family. These genes encode small guanine nucleotide-binding proteins that stimulate the ADP-ribosyltransferase activity of cholera toxin and play a role in vesicular trafficking and as activators of phospholipase D. The gene products include 6 ARF proteins and 11 ARF-like proteins and constitute 1 family of the RAS superfamily. The ARF proteins are categorized as class I (ARF1, ARF2,and ARF3), class II (ARF4 and ARF5) and class III (ARF6). The members of each class share a common gene organization. [provided by RefSeq, Dec 2010]

LOC105375489 (HGNC:):

GCC1 (HGNC:19095): (GRIP and coiled-coil domain containing 1) The protein encoded by this gene is a peripheral membrane protein. It is sensitive to brefeldin A. This encoded protein contains a GRIP domain which is thought to be used in targeting. It may play a role in the organization of trans-Golgi network subcompartment involved with membrane transport. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.40876272).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ARF5	NM_001662.4	c.411C>A	p.Ser137Arg	missense_variant	5/6	ENST00000000233.10	NP_001653.1
LOC105375489	XR_007060513.1	n.304+770G>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ARF5	ENST00000000233.10	c.411C>A	p.Ser137Arg	missense_variant	5/6	1	NM_001662.4	ENSP00000000233	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

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

Jul 05, 2022

The c.411C>A (p.S137R) alteration is located in exon 5 (coding exon 5) of the ARF5 gene. This alteration results from a C to A substitution at nucleotide position 411, causing the serine (S) at amino acid position 137 to be replaced by an arginine (R). 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	0.75
BayesDel_addAF	Benign	-0.035	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.16	T;.
Eigen	Benign	0.14
Eigen_PC	Benign	0.11
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.94	D;D
M_CAP	Benign	0.063	D
MetaRNN	Benign	0.41	T;T
MetaSVM	Benign	-0.55	T
MutationAssessor	Benign	1.8	L;.
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-2.0	N;N
REVEL	Benign	0.23
Sift	Pathogenic	0.0	D;D
Sift4G	Benign	0.14	T;T
Polyphen		0.91	P;.
Vest4		0.57
MutPred		0.33		Gain of solvent accessibility (P = 0.0739);.;
MVP		0.75
MPC		1.4
ClinPred		0.95	D
GERP RS		3.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.64
gMVP		0.71

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: rs775287559; hg19: chr7-127231097;