Genetic Variant NM_012106.4:c.207C>A (chr16-57248643-C-A) – ACMG Classification: Pathogenic (12 pts)

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate

The NM_012106.4(ARL2BP):c.207C>A(p.Tyr69*) variant causes a stop gained, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. Y69Y) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

ARL2BP
NM_012106.4 stop_gained, splice_region

Scores

Splicing: ADA: 0.00003062

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 0.672

Publications

0 publications found

Variant links:

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]

ARL2BP links:

LOC124903697 (HGNC:):

LOC124903697 links:

PLLP (HGNC:18553): (plasmolipin) Predicted to be a structural constituent of myelin sheath. Predicted to be involved in myelination. Predicted to be located in compact myelin and membrane raft. Predicted to be integral component of membrane. Biomarker of schizophrenia. [provided by Alliance of Genome Resources, Apr 2022]

PLLP links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 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 16-57248643-C-A is Pathogenic according to our data. Variant chr16-57248643-C-A is described in ClinVar as Pathogenic. ClinVar VariationId is 2770655.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_012106.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARL2BP	NM_012106.4	MANE Select	c.207C>A	p.Tyr69*	stop_gained splice_region	Exon 3 of 6	NP_036238.1	Q9Y2Y0-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ARL2BP	ENST00000219204.8	TSL:1 MANE Select	c.207C>A	p.Tyr69*	stop_gained splice_region	Exon 3 of 6	ENSP00000219204.3	Q9Y2Y0-1
ARL2BP	ENST00000563234.1	TSL:2	c.198C>A	p.Tyr66*	stop_gained splice_region	Exon 3 of 6	ENSP00000454237.1	H3BM52
ARL2BP	ENST00000562023.5	TSL:3	c.101-1137C>A		intron	N/A	ENSP00000457465.1	H3BU49

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1369300

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

682306

African (AFR)

AF:

0.00

AC:

AN:

30140

American (AMR)

AF:

0.00

AC:

AN:

35954

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24596

East Asian (EAS)

AF:

0.00

AC:

AN:

37110

South Asian (SAS)

AF:

0.00

AC:

AN:

74730

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52410

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5548

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1051948

Other (OTH)

AF:

0.00

AC:

AN:

56864

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Pathogenic

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.63

BayesDel_noAF

Pathogenic

0.59

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

Eigen

Benign

0.12

Eigen_PC

Benign

-0.039

FATHMM_MKL

Uncertain

0.87

PhyloP100

0.67

Vest4

0.49

GERP RS

1.1

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000031

dbscSNV1_RF

Benign

0.11

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over