rs4148077

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_005050.4(ABCD4):c.910G>A(p.Ala304Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.349 in 1,613,482 control chromosomes in the GnomAD database, including 101,222 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. A304A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.31 ( 7727 hom., cov: 32)

Exomes 𝑓: 0.35 ( 93495 hom. )

Consequence

ABCD4
NM_005050.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 0.657

Publications

45 publications found

Variant links:

Genes affected

ABCD4 (HGNC:68): (ATP binding cassette subfamily D member 4) 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. The function of this peroxisomal membrane protein is unknown. However, it is speculated that it may function as a heterodimer for another peroxisomal ABC transporter and, therefore, may modify the adrenoleukodystrophy phenotype. It may also play a role in the process of peroxisome biogenesis. Alternative splicing results in several protein-coding and non-protein-coding variants. [provided by RefSeq, Jul 2017]

ABCD4 Gene-Disease associations (from GenCC):

methylmalonic acidemia with homocystinuria, type cblJ
Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics, Orphanet, ClinGen

ABCD4 links:

ENSG00000258559 (HGNC:):

ENSG00000258559 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=7.3361397E-4).

BP6

Variant 14-74292774-C-T is Benign according to our data. Variant chr14-74292774-C-T is described in ClinVar as Benign. ClinVar VariationId is 259621.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.366 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005050.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ABCD4	NM_005050.4	MANE Select	c.910G>A	p.Ala304Thr	missense	Exon 9 of 19	NP_005041.1	O14678
ABCD4	NM_020325.3		c.910G>A	p.Ala304Thr	missense	Exon 9 of 18	NP_064730.1
ABCD4	NM_001440752.1		c.910G>A	p.Ala304Thr	missense	Exon 9 of 18	NP_001427681.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ABCD4	ENST00000356924.9	TSL:1 MANE Select	c.910G>A	p.Ala304Thr	missense	Exon 9 of 19	ENSP00000349396.4	O14678
ABCD4	ENST00000460308.6	TSL:1	n.*516G>A		non_coding_transcript_exon	Exon 7 of 9	ENSP00000436527.2	E9PI46
ABCD4	ENST00000469672.5	TSL:1	n.*436G>A		non_coding_transcript_exon	Exon 6 of 9	ENSP00000434626.1	E9PPB6

Frequencies

GnomAD3 genomes

AF:

0.309

AC:

46920

AN:

151914

Hom.:

7737

Cov.:

show subpopulations

Gnomad AFR

AF:

0.191

Gnomad AMI

AF:

0.468

Gnomad AMR

AF:

0.306

Gnomad ASJ

AF:

0.442

Gnomad EAS

AF:

0.251

Gnomad SAS

AF:

0.361

Gnomad FIN

AF:

0.311

Gnomad MID

AF:

0.560

Gnomad NFE

AF:

0.370

Gnomad OTH

AF:

0.362

GnomAD2 exomes

AF:

0.327

AC:

81980

AN:

250620

AF XY:

0.340

show subpopulations

Gnomad AFR exome

AF:

0.187

Gnomad AMR exome

AF:

0.224

Gnomad ASJ exome

AF:

0.437

Gnomad EAS exome

AF:

0.242

Gnomad FIN exome

AF:

0.311

Gnomad NFE exome

AF:

0.372

Gnomad OTH exome

AF:

0.374

GnomAD4 exome

AF:

0.353

AC:

515615

AN:

1461452

Hom.:

93495

Cov.:

AF XY:

0.356

AC XY:

258789

AN XY:

726972

show subpopulations

African (AFR)

AF:

0.185

AC:

6191

AN:

33474

American (AMR)

AF:

0.231

AC:

10332

AN:

44652

Ashkenazi Jewish (ASJ)

AF:

0.444

AC:

11600

AN:

26130

East Asian (EAS)

AF:

0.242

AC:

9600

AN:

39692

South Asian (SAS)

AF:

0.371

AC:

32019

AN:

86230

European-Finnish (FIN)

AF:

0.314

AC:

16776

AN:

53394

Middle Eastern (MID)

AF:

0.525

AC:

3031

AN:

5768

European-Non Finnish (NFE)

AF:

0.364

AC:

404332

AN:

1111732

Other (OTH)

AF:

0.360

AC:

21734

AN:

60380

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

20166

40332

60497

80663

100829

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

12600

25200

37800

50400

63000

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.309

AC:

46915

AN:

152030

Hom.:

7727

Cov.:

AF XY:

0.306

AC XY:

22763

AN XY:

74316

show subpopulations

African (AFR)

AF:

0.191

AC:

7922

AN:

41452

American (AMR)

AF:

0.305

AC:

4664

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.442

AC:

1536

AN:

3472

East Asian (EAS)

AF:

0.251

AC:

1294

AN:

5156

South Asian (SAS)

AF:

0.360

AC:

1725

AN:

4796

European-Finnish (FIN)

AF:

0.311

AC:

3288

AN:

10588

Middle Eastern (MID)

AF:

0.562

AC:

164

AN:

292

European-Non Finnish (NFE)

AF:

0.370

AC:

25132

AN:

67982

Other (OTH)

AF:

0.362

AC:

764

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1663

3326

4990

6653

8316

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

468

936

1404

1872

2340

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.350

Hom.:

22387

Bravo

AF:

0.300

TwinsUK

AF:

0.366

AC:

1357

ALSPAC

AF:

0.355

AC:

1367

ESP6500AA

AF:

0.197

AC:

870

ESP6500EA

AF:

0.364

AC:

3129

ExAC

AF:

0.327

AC:

39709

Asia WGS

AF:

0.311

AC:

1079

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Methylmalonic acidemia with homocystinuria, type cblJ (2)

not specified (2)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.086

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.16

CADD

Benign

(source)

DANN

Benign

0.88

DEOGEN2

Benign

0.040

Eigen

Benign

-0.83

Eigen_PC

Benign

-0.67

FATHMM_MKL

Benign

0.33

LIST_S2

Benign

0.85

MetaRNN

Benign

0.00073

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.90

PhyloP100

0.66

PrimateAI

Benign

0.24

PROVEAN

Benign

-0.30

REVEL

Uncertain

0.34

Sift

Benign

0.86

Sift4G

Benign

0.74

Polyphen

0.0030

Vest4

0.024

MPC

0.24

ClinPred

0.0050

GERP RS

2.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.028

gMVP

0.58

Mutation Taster

=90/10

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over