7-12688340-A-C

Position:

• chr7-12688340-A-C

Variant summary

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

The NM_005738.5(ARL4A):​c.86A>C​(p.Asp29Ala) 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: 33)
• Consequence: ARL4A NM_005738.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.23

Genes affected

ARL4A (HGNC:695): (ADP ribosylation factor like GTPase 4A) ADP-ribosylation factor-like 4A is a member of the ADP-ribosylation factor family of GTP-binding proteins. ARL4A is similar to ARL4C and ARL4D and each has a nuclear localization signal and an unusually high guaninine nucleotide exchange rate. ARL4A is located in both the nuclear and extranuclear cell compartments. Multiple transcript variants encoding the same protein have been found for this gene. [provided by RefSeq, Jul 2008]

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, 0.983

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ARL4A	NM_005738.5	c.86A>C	p.Asp29Ala	missense_variant	2/2	ENST00000651779.1	NP_005729.1
ARL4A	NM_001037164.3	c.86A>C	p.Asp29Ala	missense_variant	2/2		NP_001032241.1
ARL4A	NM_001195396.2	c.86A>C	p.Asp29Ala	missense_variant	2/2		NP_001182325.1
ARL4A	NM_212460.4	c.86A>C	p.Asp29Ala	missense_variant	2/2		NP_997625.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ARL4A	ENST00000651779.1	c.86A>C	p.Asp29Ala	missense_variant	2/2		NM_005738.5	ENSP00000498350	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

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

Mar 25, 2024

The c.86A>C (p.D29A) alteration is located in exon 2 (coding exon 1) of the ARL4A gene. This alteration results from a A to C substitution at nucleotide position 86, causing the aspartic acid (D) at amino acid position 29 to be replaced by an alanine (A). 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	0.99
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.32
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.61	D;D;D;.;D;D
Eigen	Pathogenic	0.94
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	.;.;.;D;D;.
M_CAP	Uncertain	0.22	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D
MetaSVM	Uncertain	0.76	D
MutationAssessor	Uncertain	2.6	M;M;M;.;M;M
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.72	T
PROVEAN	Pathogenic	-7.9	D;D;D;D;D;D
REVEL	Pathogenic	0.92
Sift	Pathogenic	0.0	D;D;D;D;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D;D;D
Polyphen		1.0	D;D;D;.;D;D
Vest4		0.74
MutPred		0.89		Gain of ubiquitination at K33 (P = 0.0685);Gain of ubiquitination at K33 (P = 0.0685);Gain of ubiquitination at K33 (P = 0.0685);Gain of ubiquitination at K33 (P = 0.0685);Gain of ubiquitination at K33 (P = 0.0685);Gain of ubiquitination at K33 (P = 0.0685);
MVP		0.87
MPC		1.8
ClinPred		1.0	D
GERP RS		4.9
Varity_R		0.97
gMVP		0.73

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: chr7-12727965;