12-101396497-C-T

Variant names:

• chr12-101396497-C-T
• rs199895049
• NM_001177.6:c.417G>A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001177.6(ARL1):​c.417G>A​(p.Met139Ile) variant causes a missense change. The variant allele was found at a frequency of 0.000211 in 1,613,856 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00022 (0 hom.)
• Consequence: ARL1 NM_001177.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.84

Genes affected

ARL1 (HGNC:692): (ADP ribosylation factor like GTPase 1) The protein encoded by this gene belongs to the ARL (ADP-ribosylation factor-like) family of proteins, which are structurally related to ADP-ribosylation factors (ARFs). ARFs, described as activators of cholera toxin (CT) ADP-ribosyltransferase activity, regulate intracellular vesicular membrane trafficking, and stimulate a phospholipase D (PLD) isoform. Although, ARL proteins were initially thought not to activate CT or PLD, later work showed that they are weak stimulators of PLD and CT in a phospholipid dependent manner. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jul 2014]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06744954).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARL1	NM_001177.6	c.417G>A	p.Met139Ile	missense_variant	Exon 5 of 6	ENST00000261636.13	NP_001168.1
ARL1	NM_001301068.1	c.279G>A	p.Met93Ile	missense_variant	Exon 4 of 5		NP_001287997.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARL1	ENST00000261636.13	c.417G>A	p.Met139Ile	missense_variant	Exon 5 of 6	1	NM_001177.6	ENSP00000261636.8

Frequencies

GnomAD3 genomes AF: 0.000112 AC: 17 AN: 152146 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

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: 0.000220

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000132 AC: 33 AN: 249278 Hom.: 0 AF XY: 0.000140 AC XY: 19 AN XY: 135244

Gnomad AFR exome AF: 0.0000646

Gnomad AMR exome AF: 0.0000869

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000464

Gnomad NFE exome AF: 0.000248

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000222 AC: 324 AN: 1461710 Hom.: 0 Cov.: 31 AF XY: 0.000223 AC XY: 162 AN XY: 727138

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000375

Gnomad4 NFE exome AF: 0.000283

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome AF: 0.000112 AC: 17 AN: 152146 Hom.: 0 Cov.: 32 AF XY: 0.0000942 AC XY: 7 AN XY: 74320

Gnomad4 AFR AF: 0.0000483

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: 0.000220

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000158 Hom.: 0

Bravo AF: 0.000125

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000241 AC: 2

ExAC AF: 0.000108 AC: 13

EpiCase AF: 0.000382

EpiControl AF: 0.000178

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 27, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.417G>A (p.M139I) alteration is located in exon 5 (coding exon 5) of the ARL1 gene. This alteration results from a G to A substitution at nucleotide position 417, causing the methionine (M) at amino acid position 139 to be replaced by an isoleucine (I). 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	0.19
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	22
DANN	Benign	0.78
DEOGEN2	Benign	0.11	T;T;.;T;.;T
Eigen	Benign	-0.56
Eigen_PC	Benign	-0.18
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.88	D;D;.;D;D;D
M_CAP	Benign	0.0016	T
MetaRNN	Benign	0.067	T;T;T;T;T;T
MetaSVM	Benign	-0.85	T
MutationAssessor	Benign	-2.4	N;.;.;.;.;.
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	2.0	N;N;N;N;N;N
REVEL	Benign	0.13
Sift	Benign	1.0	T;T;T;T;T;T
Sift4G	Benign	1.0	T;T;T;T;T;T
Polyphen		0.0	B;B;.;.;.;B
Vest4		0.39
MutPred		0.42		Gain of catalytic residue at N141 (P = 0.0401);.;.;.;.;Gain of catalytic residue at N141 (P = 0.0401);
MVP		0.58
MPC		1.3
ClinPred		0.21	T
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.49
gMVP		0.76

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: rs199895049; hg19: chr12-101790275;