Variant 7-12688829-T-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_005738.5(ARL4A):c.575T>C(p.Met192Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000311 in 1,607,136 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

ARL4A
NM_005738.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.29

Variant links:

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]

ARL4A links:

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ACMG classification

Classification made for transcript

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=0.17697352).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ARL4A	NM_005738.5 link	c.575T>C	p.Met192Thr	missense_variant	2/2	ENST00000651779.1	NP_005729.1	P40617A0A024R9Z2
ARL4A	NM_001037164.3 link	c.575T>C	p.Met192Thr	missense_variant	2/2		NP_001032241.1	P40617A0A024R9Z2
ARL4A	NM_001195396.2 link	c.575T>C	p.Met192Thr	missense_variant	2/2		NP_001182325.1	P40617A0A024R9Z2
ARL4A	NM_212460.4 link	c.575T>C	p.Met192Thr	missense_variant	2/2		NP_997625.1	P40617A0A024R9Z2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ARL4A	ENST00000651779.1 link	c.575T>C	p.Met192Thr	missense_variant	2/2		NM_005738.5	ENSP00000498350.1		P40617

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

152010

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000275

AC:

AN:

1455126

Hom.:

Cov.:

AF XY:

0.00000276

AC XY:

AN XY:

723750

show subpopulations

Gnomad4 AFR exome

AF:

0.0000305

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.0000167

GnomAD4 genome

AF:

0.00000658

AC:

AN:

152010

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74224

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 04, 2023

The c.575T>C (p.M192T) alteration is located in exon 2 (coding exon 1) of the ARL4A gene. This alteration results from a T to C substitution at nucleotide position 575, causing the methionine (M) at amino acid position 192 to be replaced by a threonine (T). 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

0.15

BayesDel_addAF

Benign

-0.013

BayesDel_noAF

Benign

-0.26

CADD

Benign

DANN

Benign

0.73

DEOGEN2

Benign

0.14

T;T;T;T;T

Eigen

Benign

-0.12

Eigen_PC

Benign

0.068

FATHMM_MKL

Uncertain

0.88

LIST_S2

Benign

0.75

.;.;.;T;.

M_CAP

Benign

0.023

MetaRNN

Benign

0.18

T;T;T;T;T

MetaSVM

Benign

-0.84

MutationAssessor

Benign

0.38

N;N;N;N;N

PrimateAI

Pathogenic

0.85

PROVEAN

Benign

-1.0

N;N;N;N;N

REVEL

Benign

0.15

Sift

Benign

0.42

T;T;T;T;T

Sift4G

Benign

0.47

T;T;T;T;T

Polyphen

0.024

B;B;B;B;B

Vest4

0.48

MutPred

0.48

Gain of phosphorylation at M192 (P = 0.0033);Gain of phosphorylation at M192 (P = 0.0033);Gain of phosphorylation at M192 (P = 0.0033);Gain of phosphorylation at M192 (P = 0.0033);Gain of phosphorylation at M192 (P = 0.0033);

MVP

0.39

MPC

0.72

ClinPred

0.63

GERP RS

4.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Varity_R

0.33

gMVP

0.46

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over