rs72554634

Positions:

• chrX-75071516-A-C
• chrX-75071516-A-G
• chrX-75071516-A-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Moderate PP5_Moderate

The NM_001271696.3(ABCB7):​c.1200T>G​(p.Ile400Met) variant causes a missense change involving the alteration of a non-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 (★).

• Frequency: Genomes: not found (cov: 22)
• Consequence: ABCB7 NM_001271696.3 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2 O:1
• Conservation: PhyloP100: 1.44

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 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.85
• PP5: Variant X-75071516-A-C is Pathogenic according to our data. Variant chrX-75071516-A-C is described in ClinVar as [Pathogenic]. Clinvar id is 11574.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-75071516-A-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ABCB7	NM_001271696.3	c.1200T>G	p.Ile400Met	missense_variant	9/16	ENST00000373394.8	NP_001258625.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ABCB7	ENST00000373394.8	c.1200T>G	p.Ile400Met	missense_variant	9/16	1	NM_001271696.3	ENSP00000362492.3

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 22

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

X-linked sideroblastic anemia with ataxia Pathogenic:1 Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	May 01, 1999	- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Nov 15, 2012

p.Ile401Met (ATT>ATG): c.1203 T>G in exon 9 of the ABCB7 gene (NM_004299.3). The I401M missense mutation in the ABCB7 gene has been reported previously in association with X-linked sideroblastic anemia in a family in which five male members were affected (Allikmets et al., 1999). In vitro studies using a yeast model found that the I401M mutation results in a partial loss of function of the yeast Atm1 protein (Allikmets et al., 1999). This result is consistent with a diagnosis of X-linked sideroblastic anemia. The variant is found in MITONUC-MITOP panel(s). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.42
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.45
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.73	.;.;.;.;D;T;.
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.99	.;D;D;D;D;D;D
M_CAP	Uncertain	0.20	D
MetaRNN	Pathogenic	0.85	D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.85	D
MutationAssessor	Pathogenic	3.2	.;.;.;.;M;.;.
PrimateAI	Uncertain	0.68	T
PROVEAN	Uncertain	-3.0	.;D;.;D;D;.;D
REVEL	Pathogenic	0.82
Sift	Uncertain	0.0010	.;D;.;D;D;.;D
Sift4G	Pathogenic	0.0010	.;D;.;D;D;D;D
Polyphen		1.0	D;D;.;.;D;.;.
Vest4		0.88, 0.80, 0.88, 0.79
MutPred		0.69		.;.;.;.;Loss of catalytic residue at L405 (P = 0.0841);.;.;
MVP		0.95
MPC		2.3
ClinPred		0.99	D
GERP RS		1.0
Varity_R		0.97
gMVP		0.98

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs72554634; hg19: chrX-74291351;