1-94458618-G-A

Position:

• chr1-94458618-G-A

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BP6

The NM_002858.4(ABCD3):​c.122G>A​(p.Gly41Glu) variant causes a missense change. The variant allele was found at a frequency of 0.000646 in 1,612,582 control chromosomes in the GnomAD database, including 1 homozygotes. 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: 𝑓 0.00043 (0 hom., cov: 30)
  • Exomes 𝑓: 0.00067 (1 hom.)
• Consequence: ABCD3 NM_002858.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 6.00

Genes affected

ABCD3 (HGNC:67): (ATP binding cassette subfamily D member 3) 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 likely plays an important role in peroxisome biogenesis. Mutations have been associated with some forms of Zellweger syndrome, a heterogeneous group of peroxisome assembly disorders. Alternative splicing results in multiple transcript variants encoding distinct isoforms. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_benign. Variant got -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15749678).
• BP6: Variant 1-94458618-G-A is Benign according to our data. Variant chr1-94458618-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 2039463.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ABCD3	NM_002858.4	c.122G>A	p.Gly41Glu	missense_variant	2/23	ENST00000370214.9	NP_002849.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ABCD3	ENST00000370214.9	c.122G>A	p.Gly41Glu	missense_variant	2/23	1	NM_002858.4	ENSP00000359233	P3
ABCD3	ENST00000315713.5	c.122G>A	p.Gly41Glu	missense_variant	2/9	1		ENSP00000326880
ABCD3	ENST00000647998.2	c.122G>A	p.Gly41Glu	missense_variant	2/23			ENSP00000497921	A1
ABCD3	ENST00000468860.1	n.199G>A		non_coding_transcript_exon_variant	3/8	3

Frequencies

GnomAD3 genomes AF: 0.000434 AC: 66 AN: 152016 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000824

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.000291 AC: 73 AN: 251148 Hom.: 0 AF XY: 0.000273 AC XY: 37 AN XY: 135738

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.0000993

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000555

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000668 AC: 975 AN: 1460566 Hom.: 1 Cov.: 30 AF XY: 0.000618 AC XY: 449 AN XY: 726688

Gnomad4 AFR exome AF: 0.0000897

Gnomad4 AMR exome AF: 0.0000895

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000374

Gnomad4 NFE exome AF: 0.000823

Gnomad4 OTH exome AF: 0.000862

GnomAD4 genome AF: 0.000434 AC: 66 AN: 152016 Hom.: 0 Cov.: 30 AF XY: 0.000431 AC XY: 32 AN XY: 74234

Gnomad4 AFR AF: 0.000217

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000824

Gnomad4 OTH AF: 0.000479

Alfa AF: 0.000692 Hom.: 0

Bravo AF: 0.000393

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000931 AC: 8

ExAC AF: 0.000313 AC: 38

EpiCase AF: 0.000763

EpiControl AF: 0.000415

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2023	ABCD3: PM2, PP3 -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 03, 2023	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.034	T
BayesDel_noAF	Uncertain	0.070
CADD	Benign	22
DANN	Benign	0.79
DEOGEN2	Benign	0.32	.;T;.
Eigen	Uncertain	0.21
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.79	.;T;T
M_CAP	Pathogenic	0.44	D
MetaRNN	Benign	0.16	T;T;T
MetaSVM	Pathogenic	0.81	D
MutationAssessor	Uncertain	2.2	.;M;M
MutationTaster	Benign	1.0	D;D;D;D;N
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	0.74	.;N;N
REVEL	Uncertain	0.45
Sift	Benign	0.79	.;T;T
Sift4G	Benign	1.0	.;T;T
Polyphen		1.0	.;D;D
Vest4		0.59, 0.59
MVP		0.71
MPC		0.73
ClinPred		0.051	T
GERP RS		5.3
Varity_R		0.24
gMVP		0.39

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: rs75418934; hg19: chr1-94924174;