5-176371758-C-T

Position:

• chr5-176371758-C-T

Variant summary

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

The NM_173664.6(ARL10):​c.598C>T​(p.Arg200Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000041 in 1,461,872 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: ARL10 NM_173664.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.48

Genes affected

ARL10 (HGNC:22042): (ADP ribosylation factor like GTPase 10) Predicted to enable GTP binding activity and GTPase activity. [provided by Alliance of Genome Resources, Apr 2022]

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=0.31335068).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ARL10	NM_173664.6	c.598C>T	p.Arg200Trp	missense_variant	4/4	ENST00000310389.6	NP_775935.1
ARL10	XM_011534529.4	c.561+2776C>T		intron_variant			XP_011532831.1
ARL10	XM_011534530.4	c.561+2776C>T		intron_variant			XP_011532832.1
ARL10	XM_011534531.4	c.562-464C>T		intron_variant			XP_011532833.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ARL10	ENST00000310389.6	c.598C>T	p.Arg200Trp	missense_variant	4/4	2	NM_173664.6	ENSP00000308496.5
ARL10	ENST00000503175.1	c.36+2776C>T		intron_variant		3		ENSP00000424831.1
ARL10	ENST00000514533.1	c.132+2776C>T		intron_variant		3		ENSP00000421449.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000410 AC: 6 AN: 1461872 Hom.: 0 Cov.: 30 AF XY: 0.00000413 AC XY: 3 AN XY: 727242

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000450

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

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

Oct 01, 2024

The c.598C>T (p.R200W) alteration is located in exon 4 (coding exon 4) of the ARL10 gene. This alteration results from a C to T substitution at nucleotide position 598, causing the arginine (R) at amino acid position 200 to be replaced by a tryptophan (W). 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	0.11
BayesDel_addAF	Benign	-0.030	T
BayesDel_noAF	Benign	-0.28
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.20	T
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.85	D
M_CAP	Uncertain	0.096	D
MetaRNN	Benign	0.31	T
MetaSVM	Benign	-0.79	T
MutationAssessor	Benign	1.1	L
PrimateAI	Benign	0.22	T
PROVEAN	Uncertain	-3.5	D
REVEL	Uncertain	0.30
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.24
MutPred		0.54		Gain of catalytic residue at L198 (P = 0.0054);
MVP		0.90
MPC		1.3
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.32
gMVP		0.46

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.15		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: rs769324573; hg19: chr5-175798761; COSMIC: COSV59991051; COSMIC: COSV59991051;