chr12-122935407-C-A

Variant names:

• chr12-122935407-C-A
• rs763436577
• NM_019625.4:c.1768G>T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_019625.4(ABCB9):​c.1768G>T​(p.Val590Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,420 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ABCB9 NM_019625.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.85

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.771

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCB9	NM_019625.4	c.1768G>T	p.Val590Leu	missense_variant	Exon 10 of 12	ENST00000280560.13	NP_062571.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ABCB9	ENST00000280560.13	c.1768G>T	p.Val590Leu	missense_variant	Exon 10 of 12	1	NM_019625.4	ENSP00000280560.8

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461420 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 727014

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 02, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1768G>T (p.V590L) alteration is located in exon 10 (coding exon 9) of the ABCB9 gene. This alteration results from a G to T substitution at nucleotide position 1768, causing the valine (V) at amino acid position 590 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	0.37
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.17
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.74	.;.;D;.;.;D;D;D;D;D
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	D;D;.;D;D;.;D;D;D;D
M_CAP	Uncertain	0.27	D
MetaRNN	Pathogenic	0.77	D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.62	D
MutationAssessor	Benign	0.77	N;N;N;.;.;N;.;N;.;.
PrimateAI	Uncertain	0.75	T
PROVEAN	Uncertain	-2.7	D;D;D;D;D;D;D;D;D;N
REVEL	Pathogenic	0.77
Sift	Uncertain	0.0050	D;D;D;D;D;D;D;D;D;T
Sift4G	Uncertain	0.014	D;D;D;D;D;D;D;D;.;D
Polyphen		0.32, 0.28	.;.;B;.;B;B;.;B;.;.
Vest4		0.87
MutPred		0.53		Gain of catalytic residue at E588 (P = 0.0034);Gain of catalytic residue at E588 (P = 0.0034);Gain of catalytic residue at E588 (P = 0.0034);.;.;Gain of catalytic residue at E588 (P = 0.0034);Gain of catalytic residue at E588 (P = 0.0034);Gain of catalytic residue at E588 (P = 0.0034);.;.;
MVP		0.98
MPC		0.50
ClinPred		0.98	D
GERP RS		5.0
Varity_R		0.58
gMVP		0.68

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

LitVar

Other links and lift over

dbSNP: rs763436577; hg19: chr12-123419954;