chr12-122981204-A-C

Position:

• chr12-122981204-A-C

Variant summary

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

The ENST00000315580.10(ARL6IP4):​c.65A>C​(p.Glu22Ala) 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. 12/20 in silico tools predict a benign outcome for this variant. 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. E22V) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: ARL6IP4 ENST00000315580.10 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.560

Genes affected

ARL6IP4 (HGNC:18076): (ADP ribosylation factor like GTPase 6 interacting protein 4) Enables identical protein binding activity. Predicted to be involved in RNA splicing and mRNA processing. Predicted to be located in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ABCB9 (HGNC:50): (ATP binding cassette subfamily B member 9) The membrane-associated protein encoded by this gene is a member of the superfamily of ATP-binding cassette (ABC) transporters. ABC proteins transport various molecules across extra- and intra-cellular membranes. ABC genes are divided into seven distinct subfamilies (ABC1, MDR/TAP, MRP, ALD, OABP, GCN20, White). This protein is a member of the MDR/TAP subfamily. Members of the MDR/TAP subfamily are involved in multidrug resistance as well as antigen presentation. This family member functions in the translocation of peptides from the cytosol into the lysosomal lumen. Alternative splicing of this gene results in distinct isoforms which are likely to have different substrate specificities. [provided by RefSeq, Jul 2011]

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=0.19360176).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ARL6IP4	NM_018694.4	c.65A>C	p.Glu22Ala	missense_variant	2/6	ENST00000315580.10	NP_061164.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ARL6IP4	ENST00000315580.10	c.65A>C	p.Glu22Ala	missense_variant	2/6	1	NM_018694.4	ENSP00000313422	A1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

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

Mar 03, 2022

The c.434A>C (p.E145A) alteration is located in exon 2 (coding exon 2) of the ARL6IP4 gene. This alteration results from a A to C substitution at nucleotide position 434, causing the glutamic acid (E) at amino acid position 145 to be replaced by an alanine (A). 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	0.16
BayesDel_addAF	Benign	-0.093	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	23
DANN	Uncertain	0.98
DEOGEN2	Benign	0.011	T;.;.;T;.;.;.;.;T;T;T;.
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.28
FATHMM_MKL	Benign	0.45	N
LIST_S2	Benign	0.81	T;T;T;T;T;T;T;T;T;T;T;T
M_CAP	Benign	0.036	D
MetaRNN	Benign	0.19	T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.5	L;L;L;.;L;.;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;N;N;N;N;N;N;N;N;N
PrimateAI	Uncertain	0.49	T
PROVEAN	Uncertain	-2.7	.;.;.;D;.;N;N;N;N;N;N;N
REVEL	Benign	0.078
Sift	Uncertain	0.0050	.;.;.;D;.;D;D;D;D;D;D;D
Sift4G	Benign	0.44	T;T;T;T;T;T;T;T;T;T;T;T
Vest4		0.25
MVP		0.53
MPC		0.0077
ClinPred		0.82	D
GERP RS		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.14
gMVP		0.24

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: chr12-123465751;