16-57248574-C-CAAGTA

Position:

• chr16-57248574-C-CAAGTA

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_012106.4(ARL2BP):​c.139_143dupAAGTA​(p.Tyr48fs) variant causes a frameshift, stop gained change. The variant allele was found at a frequency of 0.00000413 in 1,452,778 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: ARL2BP NM_012106.4 frameshift, stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 5.78

Genes affected

ARL2BP (HGNC:17146): (ADP ribosylation factor like GTPase 2 binding protein) ADP-ribosylation factor (ARF)-like proteins (ARLs) comprise a functionally distinct group of the ARF family of RAS-related GTPases. The protein encoded by this gene binds to ARL2.GTP with high affinity but does not interact with ARL2.GDP, activated ARF, or RHO proteins. The lack of detectable membrane association of this protein or ARL2 upon activation of ARL2 is suggestive of actions distinct from those of the ARFs. This protein is considered to be the first ARL2-specific effector identified, due to its interaction with ARL2.GTP but lack of ARL2 GTPase-activating protein activity. [provided by RefSeq, Jul 2008]

PLLP (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 16-57248574-C-CAAGTA is Pathogenic according to our data. Variant chr16-57248574-C-CAAGTA is described in ClinVar as [Pathogenic]. Clinvar id is 1373439.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ARL2BP	NM_012106.4	c.139_143dupAAGTA	p.Tyr48fs	frameshift_variant, stop_gained	3/6	ENST00000219204.8	NP_036238.1
ARL2BP	XM_047433883.1	c.43_47dupAAGTA	p.Tyr16fs	frameshift_variant, stop_gained	3/6		XP_047289839.1
LOC124903697	XR_007065082.1	n.1482_1486dupTACTT		non_coding_transcript_exon_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ARL2BP	ENST00000219204.8	c.139_143dupAAGTA	p.Tyr48fs	frameshift_variant, stop_gained	3/6	1	NM_012106.4	ENSP00000219204.3
ARL2BP	ENST00000563234.1	c.130_134dupAAGTA	p.Tyr45fs	frameshift_variant, stop_gained	3/6	2		ENSP00000454237.1
ARL2BP	ENST00000562023.5	c.101-1205_101-1201dupAAGTA		intron_variant		3		ENSP00000457465.1
PLLP	ENST00000564376.1	n.368_372dupTACTT		non_coding_transcript_exon_variant	2/2	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000413 AC: 6 AN: 1452778 Hom.: 0 Cov.: 29 AF XY: 0.00000277 AC XY: 2 AN XY: 722392

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000541

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 17, 2021

This sequence change creates a premature translational stop signal (p.Tyr48*) in the ARL2BP gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ARL2BP are known to be pathogenic (PMID: 23849777, 27790702, 29718757, 30210231). This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals affected with ARL2BP-related conditions. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs753029079; hg19: chr16-57282486;