rs80356714

Positions:

• chrX-75070433-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PP3_Moderate PP5

The NM_001271696.3(ABCB7):​c.1297G>A​(p.Glu433Lys) 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 Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 21)
• Consequence: ABCB7 NM_001271696.3 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:2
• Conservation: PhyloP100: 7.57

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PM1: In a mutagenesis_site Loss of ATPase activity stimulation by [2Fe-2S]-(GS)4 cluster stimulation. Loss of the ability to couple MgATP binding with stimulation of ATPase activity at the nucleotide binding domain. Loss of [2Fe-2S]-(GS)4 cluster transport. (size 0) in uniprot entity ABCB7_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.922
• PP5: Variant X-75070433-C-T is Pathogenic according to our data. Variant chrX-75070433-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 11575.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chrX-75070433-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ABCB7	NM_001271696.3	c.1297G>A	p.Glu433Lys	missense_variant	10/16	ENST00000373394.8	NP_001258625.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ABCB7	ENST00000373394.8	c.1297G>A	p.Glu433Lys	missense_variant	10/16	1	NM_001271696.3	ENSP00000362492	A1

Frequencies

GnomAD3 genomes Cov.: 21

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 21

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: no assertion criteria provided

Submissions by phenotype

X-linked sideroblastic anemia with ataxia Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 01, 2000	- -
Pathogenic, no assertion criteria provided	curation	GeneReviews	Apr 07, 2009	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.66
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.70	.;.;.;.;D;T;.
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	1.0	.;D;D;D;D;D;D
M_CAP	Pathogenic	0.93	D
MetaRNN	Pathogenic	0.92	D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.2	.;.;.;.;H;.;.
MutationTaster	Benign	1.0	A;A;A
PrimateAI	Pathogenic	0.88	D
PROVEAN	Uncertain	-3.8	.;D;.;D;D;.;D
REVEL	Pathogenic	0.92
Sift	Uncertain	0.0010	.;D;.;D;D;.;D
Sift4G	Pathogenic	0.0010	.;D;.;D;D;D;D
Polyphen		1.0	D;D;.;.;D;.;.
Vest4		0.93, 0.91, 0.93, 0.91
MutPred		0.68		.;.;.;.;Gain of MoRF binding (P = 0.0191);.;.;
MVP		1.0
MPC		2.4
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.91
gMVP		0.99

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: rs80356714; hg19: chrX-74290268;