dbSNP rs80356713: ABCB7:p.Val411Leu (chrX-75070499-C-A) – ACMG Classification: Pathogenic (10 pts)

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PS1PM2PP3_ModeratePP5_Moderate

The NM_001271696.3(ABCB7):c.1231G>T(p.Val411Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in ClinVar.

Frequency

Genomes: not found (cov: 22)

Consequence

ABCB7
NM_001271696.3 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 7.57

Publications

17 publications found

Variant links:

Genes affected

ABCB7 (HGNC:48): (ATP binding cassette subfamily B member 7) 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 gene encodes a half-transporter involved in the transport of heme from the mitochondria to the cytosol. With iron/sulfur cluster precursors as its substrates, this protein may play a role in metal homeostasis. Mutations in this gene have been associated with mitochondrial iron accumulation and isodicentric (X)(q13) and sideroblastic anemia. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Nov 2012]

ABCB7 Gene-Disease associations (from GenCC):

X-linked sideroblastic anemia with ataxia
Inheritance: XL, XLR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Illumina, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet, G2P
mitochondrial disease
Inheritance: XL Classification: MODERATE Submitted by: ClinGen

ABCB7 links:

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 10 ACMG points.

PS1

Transcript NM_001271696.3 (ABCB7) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.913

PP5

Variant X-75070499-C-A is Pathogenic according to our data. Variant chrX-75070499-C-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 3235083.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCB7	NM_001271696.3 link	c.1231G>T	p.Val411Leu	missense_variant	Exon 10 of 16	ENST00000373394.8	NP_001258625.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ABCB7	ENST00000373394.8 link	c.1231G>T	p.Val411Leu	missense_variant	Exon 10 of 16	1	NM_001271696.3	ENSP00000362492.3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

X-linked sideroblastic anemia with ataxia

Pathogenic:1

Apr 25, 2024

Institute of Immunology and Genetics Kaiserslautern

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ACMG Criteria: PM2, PP3, PS1; Variant was found in hemizygous state -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.86

BayesDel_addAF

Pathogenic

0.55

BayesDel_noAF

Pathogenic

0.55

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.70

.;.;.;.;D;T;.

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.99

.;D;D;D;D;D;D

M_CAP

Pathogenic

0.87

MetaRNN

Pathogenic

0.91

D;D;D;D;D;D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

4.0

.;.;.;.;H;.;.

PhyloP100

7.6

PrimateAI

Uncertain

0.79

PROVEAN

Uncertain

-2.8

.;D;.;D;D;.;D

REVEL

Pathogenic

0.91

Sift

Uncertain

0.0080

.;D;.;D;D;.;D

Sift4G

Uncertain

0.0030

.;D;.;D;D;D;D

Polyphen

0.99

D;D;.;.;D;.;.

Vest4

0.82, 0.76, 0.82, 0.76

MutPred

0.68

.;.;.;.;Loss of catalytic residue at V411 (P = 0.1061);.;.;

MVP

0.95

MPC

2.2

ClinPred

1.0

GERP RS

5.5

Varity_R

0.94

gMVP

0.99

Mutation Taster

=6/94

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over