16-57245394-T-A

Variant names:

• chr16-57245394-T-A
• NM_012106.4:c.27T>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_012106.4(ARL2BP):​c.27T>A​(p.Phe9Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 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)
• Consequence: ARL2BP NM_012106.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.102

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.112863004).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARL2BP	NM_012106.4	c.27T>A	p.Phe9Leu	missense_variant	Exon 1 of 6	ENST00000219204.8	NP_036238.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARL2BP	ENST00000219204.8	c.27T>A	p.Phe9Leu	missense_variant	Exon 1 of 6	1	NM_012106.4	ENSP00000219204.3
ARL2BP	ENST00000563234.1	c.18T>A	p.Phe6Leu	missense_variant	Exon 1 of 6	2		ENSP00000454237.1
ARL2BP	ENST00000562023.5	c.27T>A	p.Phe9Leu	missense_variant	Exon 1 of 5	3		ENSP00000457465.1
ARL2BP	ENST00000565794.1	n.136T>A		non_coding_transcript_exon_variant	Exon 1 of 2	5

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

Inborn genetic diseases Uncertain:1

Jan 07, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.27T>A (p.F9L) alteration is located in exon 1 (coding exon 1) of the ARL2BP gene. This alteration results from a T to A substitution at nucleotide position 27, causing the phenylalanine (F) at amino acid position 9 to be replaced by a leucine (L). 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	Uncertain	0.46
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	20
DANN	Uncertain	0.98
DEOGEN2	Benign	0.027	T;.
Eigen	Benign	-0.59
Eigen_PC	Benign	-0.48
FATHMM_MKL	Benign	0.71	D
LIST_S2	Benign	0.65	T;T
M_CAP	Benign	0.032	D
MetaRNN	Benign	0.11	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.42	N;.
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-1.2	N;N
REVEL	Benign	0.050
Sift	Benign	0.29	T;T
Sift4G	Benign	0.43	T;T
Polyphen		0.0	B;.
Vest4		0.27
MutPred		0.35		Loss of sheet (P = 0.0315);Loss of sheet (P = 0.0315);
MVP		0.25
MPC		0.56
ClinPred		0.44	T
GERP RS		0.19
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.13
gMVP		0.32

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: chr16-57279306;