chr12-122980490-G-T

Position:

chr12-122980490-G-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The ENST00000542678.5(ABCB9):c.-1680C>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000659 in 1,365,232 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000025 ( 0 hom. )

Consequence

ABCB9
ENST00000542678.5 5_prime_UTR

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.451

Variant links:

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]

ARL6IP4 links:

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]

ABCB9 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.06667039).

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Protein
ARL6IP4	NM_001278379.2 linkuse as main transcript	c.-12+105G>T	intron_variant	NP_001265308.2
ARL6IP4	NM_001400281.1 linkuse as main transcript	c.-12+105G>T	intron_variant	NP_001387210.1
ARL6IP4	NM_001400282.1 linkuse as main transcript	c.-12+105G>T	intron_variant	NP_001387211.1

Ensembl

Gene	Transcript	HGVSc	Effect	#exon/exons	TSL	Protein	Appris	UniProt
ARL6IP4	ENST00000392435.7 linkuse as main transcript	c.-267G>T	5_prime_UTR_variant	1/5	1	ENSP00000376230		Q66PJ3-10
ARL6IP4	ENST00000453766.7 linkuse as main transcript	c.-267G>T	5_prime_UTR_variant	1/6	1	ENSP00000414847	A1
ABCB9	ENST00000542678.5 linkuse as main transcript	c.-1680C>A	5_prime_UTR_variant	1/12	1	ENSP00000440288	P1	Q9NP78-1

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152196

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000247

AC:

AN:

1213036

Hom.:

Cov.:

AF XY:

0.00000170

AC XY:

AN XY:

587716

show subpopulations

Gnomad4 AFR exome

AF:

0.0000395

Gnomad4 AMR exome

AF:

0.000147

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152196

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74358

show subpopulations

Gnomad4 AFR

AF:

0.0000724

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000982

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 16, 2021

The c.103G>T (p.A35S) alteration is located in exon 1 (coding exon 1) of the ARL6IP4 gene. This alteration results from a G to T substitution at nucleotide position 103, causing the alanine (A) at amino acid position 35 to be replaced by a serine (S). 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

0.12

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Benign

-0.44

CADD

Benign

3.4

DANN

Benign

0.93

DEOGEN2

Benign

0.0040

T;.;.;T;.

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.10

LIST_S2

Benign

0.46

T;T;T;T;T

M_CAP

Benign

0.0037

MetaRNN

Benign

0.067

T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

N;N;N;.;N

MutationTaster

Benign

1.0

N;N;N;N;N;N

PrimateAI

Uncertain

0.59

PROVEAN

Benign

0.10

.;.;.;N;.

REVEL

Benign

0.0050

Sift

Uncertain

0.029

.;.;.;D;.

Sift4G

Benign

0.58

T;T;T;T;T

Vest4

0.20

MVP

0.092

MPC

0.73

ClinPred

0.11

GERP RS

-1.8

RBP_binding_hub_radar

1.1

RBP_regulation_power_radar

2.3

Varity_R

0.025

gMVP

0.028

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.20

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.20

Position offset: -2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over