17-43399983-G-C

Position:

• chr17-43399983-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001661.4(ARL4D):​c.251G>C​(p.Arg84Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: ARL4D NM_001661.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.95

Genes affected

ARL4D (HGNC:656): (ADP ribosylation factor like GTPase 4D) ADP-ribosylation factor 4D is a member of the ADP-ribosylation factor family of GTP-binding proteins. ARL4D is closely similar to ARL4A and ARL4C and each has a nuclear localization signal and an unusually high guanine nucleotide exchange rate. This protein may play a role in membrane-associated intracellular trafficking. [provided by RefSeq, Jul 2021]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.957

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ARL4D	NM_001661.4	c.251G>C	p.Arg84Pro	missense_variant	2/2	ENST00000320033.5	NP_001652.2
ARL4D	XM_011524782.3	c.251G>C	p.Arg84Pro	missense_variant	2/2		XP_011523084.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ARL4D	ENST00000320033.5	c.251G>C	p.Arg84Pro	missense_variant	2/2	1	NM_001661.4	ENSP00000322628.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 31

Alfa AF: 0.0000301 Hom.: 0

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

Apr 22, 2024

The c.251G>C (p.R84P) alteration is located in exon 2 (coding exon 1) of the ARL4D gene. This alteration results from a G to C substitution at nucleotide position 251, causing the arginine (R) at amino acid position 84 to be replaced by a proline (P). 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	0.98
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.40
CADD	Pathogenic	32
DANN	Uncertain	0.99
DEOGEN2	Benign	0.33	T
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Pathogenic	0.95	D
MutationAssessor	Pathogenic	3.8	H
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-6.8	D
REVEL	Pathogenic	0.75
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.92
MutPred		0.85		Loss of MoRF binding (P = 3e-04);
MVP		0.96
MPC		2.6
ClinPred		1.0	D
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.99
gMVP		1.0

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: rs2058081177; hg19: chr17-41477351;