12-122980523-A-G

Position:

• chr12-122980523-A-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The ENST00000542678.5(ABCB9):​c.-1713T>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000823 in 1,215,264 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: not found (cov: 33)
  • Exomes 𝑓: 8.2e-7 (0 hom.)
• Consequence: ABCB9 ENST00000542678.5 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.933

Genes affected

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]

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]

ENSG00000256028 (HGNC:):

ACMG classification

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=0.06540716).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ARL6IP4	NM_001400282.1	c.-12+138A>G		intron_variant			NP_001387211.1
ARL6IP4	NM_001400320.1	c.-12+138A>G		intron_variant			NP_001387249.1
ARL6IP4	NM_001400283.1	c.-12+138A>G		intron_variant			NP_001387212.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ABCB9	ENST00000542678.5	c.-1713T>C		5_prime_UTR_variant	1/12	1		ENSP00000440288.1
ARL6IP4	ENST00000453766	c.-234A>G		5_prime_UTR_variant	1/6	1		ENSP00000414847.4
ARL6IP4	ENST00000454885	c.-376A>G		5_prime_UTR_variant	1/6	1		ENSP00000396723.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 8.23e-7 AC: 1 AN: 1215264 Hom.: 0 Cov.: 31 AF XY: 0.00000170 AC XY: 1 AN XY: 589566

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: 0.0000193

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

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

Jun 29, 2022

The c.136A>G (p.T46A) alteration is located in exon 1 (coding exon 1) of the ARL6IP4 gene. This alteration results from a A to G substitution at nucleotide position 136, causing the threonine (T) at amino acid position 46 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	0.067
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	4.7
DANN	Benign	0.60
DEOGEN2	Benign	0.0026	T;.;.;T;.
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.035	N
LIST_S2	Benign	0.31	T;T;T;T;T
M_CAP	Benign	0.0012	T
MetaRNN	Benign	0.065	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N;N;N;.;N
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-0.60	.;.;.;N;.
REVEL	Benign	0.021
Sift	Benign	0.11	.;.;.;T;.
Sift4G	Benign	0.26	T;T;T;T;T
Vest4		0.21
MVP		0.040
MPC		0.78
ClinPred		0.12	T
GERP RS		-3.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.3
Varity_R		0.041
gMVP		0.049

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: chr12-123465070;