chr17-39161308-A-G

Position:

• chr17-39161308-A-G

Variant summary

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

The NM_001143968.1(ARL5C):​c.299T>C​(p.Leu100Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000214 in 1,399,556 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: ARL5C NM_001143968.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.90

Genes affected

ARL5C (HGNC:31111): (ADP ribosylation factor like GTPase 5C) Predicted to enable GTP binding activity. Predicted to be involved in intracellular protein transport; protein localization to Golgi membrane; and vesicle-mediated transport. Predicted to be active in trans-Golgi network. [provided by Alliance of Genome Resources, Apr 2022]

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=0.046228647).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ARL5C	NM_001143968.1	c.299T>C	p.Leu100Pro	missense_variant	4/6	ENST00000269586.12	NP_001137440.1
ARL5C	XM_047435964.1	c.299T>C	p.Leu100Pro	missense_variant	4/6		XP_047291920.1
ARL5C	XM_047435963.1	c.170T>C	p.Leu57Pro	missense_variant	3/4		XP_047291919.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ARL5C	ENST00000269586.12	c.299T>C	p.Leu100Pro	missense_variant	4/6	5	NM_001143968.1	ENSP00000269586.7
ARL5C	ENST00000578912.1	n.68T>C		non_coding_transcript_exon_variant	2/4	4		ENSP00000466347.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000214 AC: 3 AN: 1399556 Hom.: 0 Cov.: 32 AF XY: 0.00000435 AC XY: 3 AN XY: 690286

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000379

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

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

May 14, 2024

The c.299T>C (p.L100P) alteration is located in exon 4 (coding exon 4) of the ARL5C gene. This alteration results from a T to C substitution at nucleotide position 299, causing the leucine (L) at amino acid position 100 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	Benign	0.065
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	3.7
DANN	Benign	0.27
DEOGEN2	Benign	0.0021	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.045	N
LIST_S2	Benign	0.71	T
M_CAP	Benign	0.0098	T
MetaRNN	Benign	0.046	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.1	N
MutationTaster	Benign	0.99	N;N
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.10	N
REVEL	Benign	0.055
Sift	Benign	0.34	T
Sift4G	Benign	0.32	T
Polyphen		0.0	B
Vest4		0.12
MutPred		0.43		Gain of disorder (P = 0.0115);
MVP		0.10
ClinPred		0.051	T
GERP RS		-1.2
Varity_R		0.30
gMVP		0.46

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1385516355; hg19: chr17-37317561;