4-56518847-C-A

Variant names:

• chr4-56518847-C-A
• NM_001363794.2:c.612C>A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001363794.2(ARL9):​c.612C>A​(p.Asn204Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N204D) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ARL9 NM_001363794.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.24

Genes affected

ARL9 (HGNC:23592): (ADP ribosylation factor like GTPase 9) ARL9 is a member of the small GTPase protein family with a high degree of similarity to ARF (MIM 103180) proteins of the RAS superfamily.[supplied by OMIM, Nov 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARL9	NM_001363794.2	c.612C>A	p.Asn204Lys	missense_variant	Exon 3 of 4	ENST00000640821.3	NP_001350723.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARL9	ENST00000640821.3	c.612C>A	p.Asn204Lys	missense_variant	Exon 3 of 4	5	NM_001363794.2	ENSP00000492671.3
ARL9	ENST00000360096.3	c.186C>A	p.Asn62Lys	missense_variant	Exon 3 of 4	1		ENSP00000353210.2
ARL9	ENST00000645327.1	n.*107C>A		non_coding_transcript_exon_variant	Exon 2 of 3			ENSP00000496178.1
ARL9	ENST00000645327.1	n.*107C>A		3_prime_UTR_variant	Exon 2 of 3			ENSP00000496178.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 08, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.186C>A (p.N62K) alteration is located in exon 3 (coding exon 2) of the ARL9 gene. This alteration results from a C to A substitution at nucleotide position 186, causing the asparagine (N) at amino acid position 62 to be replaced by a lysine (K). 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
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.050
CADD	Uncertain	25
DANN	Uncertain	1.0
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Uncertain	0.92	D;D
M_CAP	Uncertain	0.11	D
MetaRNN	Uncertain	0.60	D;D
MetaSVM	Uncertain	0.41	D
PrimateAI	Benign	0.42	T
REVEL	Uncertain	0.49
Sift4G	Pathogenic	0.0	D;.
Vest4		0.86
MVP		0.80
MPC		0.40
ClinPred		0.96	D
GERP RS		4.3
gMVP		0.83

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: chr4-57385013;