X-153743022-T-C

Position:

• chrX-153743022-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PM1 PM2 BP4_Strong

The NM_000033.4(ABCD1):​c.1816T>C​(p.Ser606Pro) variant causes a missense change. 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 Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 25)
• Consequence: ABCD1 NM_000033.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:3 B:4
• Conservation: PhyloP100: 5.17

Genes affected

ABCD1 (HGNC:61): (ATP binding cassette subfamily D member 1) The 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 ALD subfamily, which is involved in peroxisomal import of fatty acids and/or fatty acyl-CoAs in the organelle. All known peroxisomal ABC transporters are half transporters which require a partner half transporter molecule to form a functional homodimeric or heterodimeric transporter. This peroxisomal membrane protein is likely involved in the peroxisomal transport or catabolism of very long chain fatty acids. Defects in this gene have been identified as the underlying cause of adrenoleukodystrophy, an X-chromosome recessively inherited demyelinating disorder of the nervous system. [provided by RefSeq, Jul 2008]

PLXNB3-AS1 (HGNC:40454): (PLXNB3 antisense RNA 1)

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM1: In a domain ABC transporter (size 226) in uniprot entity ABCD1_HUMAN there are 27 pathogenic changes around while only 0 benign (100%) in NM_000033.4
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.019254386).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ABCD1	NM_000033.4	c.1816T>C	p.Ser606Pro	missense_variant	8/10	ENST00000218104.6	NP_000024.2
ABCD1	XM_047441916.1	c.2116T>C	p.Ser706Pro	missense_variant	9/11		XP_047297872.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ABCD1	ENST00000218104.6	c.1816T>C	p.Ser606Pro	missense_variant	8/10	1	NM_000033.4	ENSP00000218104	P1
PLXNB3-AS1	ENST00000434284.1	n.72-4444A>G		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes Cov.: 25

GnomAD3 exomes AF: 0.000381 AC: 57 AN: 149800 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 45920

Gnomad AFR exome AF: 0.000772

Gnomad AMR exome AF: 0.000333

Gnomad ASJ exome AF: 0.000454

Gnomad EAS exome AF: 0.000419

Gnomad SAS exome AF: 0.000196

Gnomad FIN exome AF: 0.000217

Gnomad NFE exome AF: 0.000423

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 25

Alfa AF: 0.0402 Hom.: 0

ExAC AF: 0.00785 AC: 945

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:3 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Adrenoleukodystrophy Pathogenic:1 Uncertain:2 Benign:3

Uncertain significance, criteria provided, single submitter	curation	SIB Swiss Institute of Bioinformatics	Oct 12, 2023	This variant is interpreted as a variant of uncertain significance, for Adrenoleukodystrophy, in X-linked Recessive manner. The following ACMG Tag(s) were applied: PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product. PS3 => Well-established functional studies show a deleterious effect (PMID:8651290) (PMID:17542813) (PMID:21966424). -
Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	May 12, 2023	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 21, 2022	In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Ser606 amino acid residue in ABCD1. Other variant(s) that disrupt this residue have been determined to be pathogenic (Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on ABCD1 function (PMID: 8651290, 17542813). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 218422). This sequence change replaces serine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 606 of the ABCD1 protein (p.Ser606Pro). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with adrenoleukodystrophy and/or adrenomyeloneuropathy (PMID: 8651290, 21700483, 21966424). In at least one individual the variant was observed to be de novo. -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

X-linked cerebral adrenoleukodystrophy Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

ABCD1, c.1816T>C, p.Ser606Pro, Hemizygous, Uncertain SignificanceThe ABCD1 p.Ser606Pro variant was identified in the literature however the frequency of this variant in an affected population was not provided. The variant was identified in dbSNP (ID: rs201774661) as Conflicting intepretations of pathogencity (Adrenoleukodystrophy), ClinVar (Conflicting interpretations of pathogenicity. Classified as likely pathogenic by Swiss Institute of Bioinformatics in 2018. Likely benign by Children's Hospital of Philadelphia in 2015, Illumina in 2016. Benign by Mendelics in 2019), and  LOVD 3.0 (Two entries, one as VUS, one unclassified)  databases. The variant was identified in control databases in 120 of 163177 chromosomes at a frequency of 0.0007354 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: African in 25 of 13442 chromosomes (freq: 0.00186), East Asian in 11 of 12400 chromosomes (freq: 0.000887), European (Finnish) in 12 of 15417 chromosomes (freq: 0.000778), European (non-Finnish) in 53 of 71204 chromosomes (freq: 0.000744), Ashkenazi Jewish in 4 of 6757 chromosomes (freq: 0.000592), Latino in 11 of 24333 chromosomes (freq: 0.000452), Other in 1 of 4316 chromosomes (freq: 0.000232), and South Asian in 3 of 15308 chromosomes (freq: 0.000196). However, the variant was only identified in females and in no males; ABCD1 is associated with X-linked recessive adrenomyeloneuropathy. The c.1816T>C variant was reported in an 11-year-old male of Indian origin with adolescent onset cerebral andrenomyeloneuropathy. Western blot indicated that the p.Ser606Pro variant resulted in no ALDP protein expression in the patient's peripheral blood mononuclear cells. (Kumar_2011_PMID:21966424) The c.1816T>C variant was identified in a Chinese patient with adrenoleukodystrophy, who was also found to have c.1028G>T and c.1814C>T variants. The proband's mother was found to be heterozygous for the c.1028G>T variant, and homozygous for the c.1814C>T and c.1816T>C variants. (Niu_2013_PMID:23566833) The p.Ser606 residue is conserved in mammals but not in more distantly related organisms, and 8 of 9 computational analyses (PolyPhen-2, SIFT, AlignGVGD, MutationTaster, DANN, MT, HATHMM, MetaLR, Revel) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.Disease Information: X-linked adrenoleukodystrophy (X-ALD) affects the nervous system white matter and the adrenal cortex. Adrenoleukodystrophy results in the apparent defect in peroxisomal beta oxidation and the accumulation of the saturated very long chain fatty acids (VLCFA) in all tissues of the body (OMIM: 300100). The manifestations of the disorder occur primarily in the adrenal cortex, the myelin of the central nervous system, and the Leydig cells of the testes (OMIM: 300100).  Adrenomyeloneuropathy (AMN) manifests most commonly in an individual in his twenties or middle age as progressive stiffness and weakness of the legs, sphincter disturbances, sexual dysfunction, and often, impaired adrenocortical function; all symptoms are progressive over decades. (Verbatim, GeneReviews) Clinical features include progressive neurodegeneration, cognitive decline, loss of speech, dementia, bulbar palsy, seizures, pararesis, spasticity, incoordination, ataxia, white matter abnormalities, sensory loss, and cerebral demyelination and inflammation. (OMIM: 300100)Familial Risk: Adrenol -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Nov 24, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.67	D
BayesDel_noAF	Pathogenic	0.72
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.99	D
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	1.0	D
MetaRNN	Benign	0.019	T
MetaSVM	Pathogenic	0.91	D
MutationAssessor	Pathogenic	3.4	M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.57	T
PROVEAN	Uncertain	-4.0	D
REVEL	Pathogenic	0.88
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0020	D
Polyphen		0.98	D
Vest4		0.26
MVP		1.0
MPC		1.7
ClinPred		0.078	T
GERP RS		5.5
Varity_R		0.97
gMVP		1.0

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: rs201774661; hg19: chrX-153008476; COSMIC: COSV54383418; COSMIC: COSV54383418;