Variant 7-151035654-T-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_007188.5(ABCB8):c.839T>C(p.Leu280Pro) variant causes a missense change. The variant allele was found at a frequency of 0.0000217 in 1,613,136 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: 𝑓 0.000026 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000021 ( 0 hom. )

Consequence

ABCB8
NM_007188.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.04

Variant links:

Genes affected

ABCB8 (HGNC:49): (ATP binding cassette subfamily B member 8) This nuclear gene encodes a multi-pass membrane protein that is targeted to the mitochondrial inner membrane. The encoded protein is an ATP-dependent transporter that may mediate the passage of organic and inorganic molecules out of the mitochondria. Loss of function of the related gene in mouse results in a disruption of iron homeostasis between the mitochondria and cytosol. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2013]

ABCB8 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.975

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCB8	NM_007188.5 link	c.839T>C	p.Leu280Pro	missense_variant	Exon 6 of 16	ENST00000358849.9	NP_009119.2	Q9NUT2-2
ABCB8	NM_001282291.2 link	c.890T>C	p.Leu297Pro	missense_variant	Exon 7 of 17		NP_001269220.1	Q9NUT2-1
ABCB8	NM_001282292.2 link	c.839T>C	p.Leu280Pro	missense_variant	Exon 6 of 16		NP_001269221.1	Q9NUT2-3
ABCB8	NM_001282293.2 link	c.575T>C	p.Leu192Pro	missense_variant	Exon 5 of 15		NP_001269222.1	Q9NUT2-4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ABCB8	ENST00000358849.9 link	c.839T>C	p.Leu280Pro	missense_variant	Exon 6 of 16	1	NM_007188.5	ENSP00000351717.4		Q9NUT2-2

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152206

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000120

AC:

AN:

250936

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135720

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000212

AC:

AN:

1460930

Hom.:

Cov.:

AF XY:

0.0000220

AC XY:

AN XY:

726708

show subpopulations

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:

0.0000270

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152206

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74354

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000565

Hom.:

Bravo

AF:

0.0000227

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Sep 22, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.839T>C (p.L280P) alteration is located in exon 6 (coding exon 6) of the ABCB8 gene. This alteration results from a T to C substitution at nucleotide position 839, causing the leucine (L) at amino acid position 280 to be replaced by a proline (P). 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

Pathogenic

0.58

BayesDel_addAF

Pathogenic

0.27

BayesDel_noAF

Pathogenic

0.17

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.60

.;.;D;.;.;D

Eigen

Uncertain

0.61

Eigen_PC

Uncertain

0.54

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.82

T;T;T;T;T;T

M_CAP

Pathogenic

0.34

MetaRNN

Pathogenic

0.97

D;D;D;D;D;D

MetaSVM

Pathogenic

0.81

MutationAssessor

Uncertain

2.9

.;.;M;.;.;.

PrimateAI

Uncertain

0.53

PROVEAN

Pathogenic

-4.5

D;D;D;D;D;D

REVEL

Pathogenic

0.84

Sift

Benign

0.074

T;T;T;T;D;D

Sift4G

Benign

0.068

T;T;T;T;D;D

Polyphen

0.89, 0.97, 0.98

.;P;D;.;.;D

Vest4

0.78

MutPred

0.84

.;.;Loss of stability (P = 0.0125);.;.;.;

MVP

1.0

MPC

0.94

ClinPred

0.96

GERP RS

4.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.81

gMVP

0.91

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

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