NM_001271696.3:c.1200T>C

Variant names:

• chrX-75071516-A-G
• rs72554634
• NM_001271696.3:c.1200T>C

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP7

The NM_001271696.3(ABCB7):​c.1200T>C​(p.Ile400Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. I400I) has been classified as Benign.

• Frequency: Genomes: not found (cov: 22)
• Consequence: ABCB7 NM_001271696.3 synonymous
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.44
• Publications: 15 publications found

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

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.63).
• BP7: Synonymous conserved (PhyloP=1.44 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001271696.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCB7	NM_001271696.3	MANE Select	c.1200T>C	p.Ile400Ile	synonymous	Exon 9 of 16	NP_001258625.1
	ABCB7	NM_004299.6		c.1203T>C	p.Ile401Ile	synonymous	Exon 9 of 16	NP_004290.2
	ABCB7	NM_001271698.3		c.1122T>C	p.Ile374Ile	synonymous	Exon 8 of 15	NP_001258627.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCB7	ENST00000373394.8	TSL:1 MANE Select	c.1200T>C	p.Ile400Ile	synonymous	Exon 9 of 16	ENSP00000362492.3
	ABCB7	ENST00000253577.9	TSL:1	c.1203T>C	p.Ile401Ile	synonymous	Exon 9 of 16	ENSP00000253577.3
	ABCB7	ENST00000620875.5	TSL:1	c.1083T>C	p.Ile361Ile	synonymous	Exon 8 of 15	ENSP00000479985.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 22

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

X-linked sideroblastic anemia with ataxia Uncertain:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.63
CADD	Benign	8.3
DANN	Benign	0.74
PhyloP100		1.4

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

Other links and lift over

dbSNP: rs72554634; hg19: chrX-74291351;