NM_000033.4:c.355G>T

Variant names:

• chrX-153725621-G-T
• rs781846746
• NM_000033.4:c.355G>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 4P and 3B. PM1 PM2 BP4 BP6_Moderate

The NM_000033.4(ABCD1):​c.355G>T​(p.Ala119Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000883 in 113,239 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A119P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000088 (0 hom., 1 hem., cov: 26)
  • Exomes 𝑓: 0.0000018 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: ABCD1 NM_000033.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 7.61
• Publications: 2 publications found

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]

BCAP31 (HGNC:16695): (B cell receptor associated protein 31) This gene encodes a member of the B-cell receptor associated protein 31 superfamily. The encoded protein is a multi-pass transmembrane protein of the endoplasmic reticulum that is involved in the anterograde transport of membrane proteins from the endoplasmic reticulum to the Golgi and in caspase 8-mediated apoptosis. Microdeletions in this gene are associated with contiguous ABCD1/DXS1375E deletion syndrome (CADDS), a neonatal disorder. Alternative splicing of this gene results in multiple transcript variants. Two related pseudogenes have been identified on chromosome 16. [provided by RefSeq, Jan 2012]

BCAP31 Gene-Disease associations (from GenCC):

• severe motor and intellectual disabilities-sensorineural deafness-dystonia syndrome

  Inheritance: AR, XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, ClinGen, G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 8 uncertain in NM_000033.4
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.41968286).
• BP6: Variant X-153725621-G-T is Benign according to our data. Variant chrX-153725621-G-T is described in ClinVar as Likely_benign. ClinVar VariationId is 1969203.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000033.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCD1	NM_000033.4	MANE Select	c.355G>T	p.Ala119Ser	missense	Exon 1 of 10	NP_000024.2
	ABCD1	NM_001440747.1		c.355G>T	p.Ala119Ser	missense	Exon 1 of 11	NP_001427676.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCD1	ENST00000218104.6	TSL:1 MANE Select	c.355G>T	p.Ala119Ser	missense	Exon 1 of 10	ENSP00000218104.3	P33897
	ABCD1	ENST00000862307.1		c.355G>T	p.Ala119Ser	missense	Exon 1 of 11	ENSP00000532366.1
	ABCD1	ENST00000862306.1		c.355G>T	p.Ala119Ser	missense	Exon 1 of 11	ENSP00000532365.1

Frequencies

GnomAD3 genomes AF: 0.00000883 AC: 1 AN: 113239 Hom.: 0 Cov.: 26

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000355

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000594 AC: 1 AN: 168250 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000183 AC: 2 AN: 1093238 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 359792

African (AFR) AF: 0.00 AC: 0 AN: 26335

American (AMR) AF: 0.00 AC: 0 AN: 34911

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19192

East Asian (EAS) AF: 0.00 AC: 0 AN: 30065

South Asian (SAS) AF: 0.0000374 AC: 2 AN: 53473

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39215

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4119

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 840063

Other (OTH) AF: 0.00 AC: 0 AN: 45865

GnomAD4 genome AF: 0.00000883 AC: 1 AN: 113239 Hom.: 0 Cov.: 26 AF XY: 0.0000283 AC XY: 1 AN XY: 35365

African (AFR) AF: 0.00 AC: 0 AN: 31275

American (AMR) AF: 0.00 AC: 0 AN: 10843

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2658

East Asian (EAS) AF: 0.00 AC: 0 AN: 3591

South Asian (SAS) AF: 0.000355 AC: 1 AN: 2820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6309

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 240

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53296

Other (OTH) AF: 0.00 AC: 0 AN: 1528

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.0000165 AC: 2

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Adrenoleukodystrophy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.92	D
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.90	D
M_CAP	Uncertain	0.20	D
MetaRNN	Benign	0.42	T
MetaSVM	Uncertain	0.27	D
MutationAssessor	Benign	0.34	N
PhyloP100		7.6
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-1.8	N
REVEL	Uncertain	0.51
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0020	D
Polyphen		0.59	P
Vest4		0.11
MutPred		0.69		Gain of phosphorylation at A119 (P = 0.0404)
MVP		0.90
MPC		0.53
ClinPred		0.49	T
GERP RS		5.4
PromoterAI		-0.0050	Neutral
Varity_R		0.57
gMVP		0.78
Mutation Taster		=92/8	polymorphism

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: rs781846746; hg19: chrX-152991076;