Genetic Variant ABCD4:p.Leu327Leu (chr14-74292598-G-T) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_005050.4(ABCD4):c.981C>A(p.Leu327Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.347 in 1,613,252 control chromosomes in the GnomAD database, including 100,815 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.30 ( 7523 hom., cov: 32)

Exomes 𝑓: 0.35 ( 93292 hom. )

Consequence

ABCD4
NM_005050.4 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.91

Publications

35 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.47).

BP6

Variant 14-74292598-G-T is Benign according to our data. Variant chr14-74292598-G-T is described in ClinVar as Benign. ClinVar VariationId is 259622.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=1.91 with no splicing effect.

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.981C>A	p.Leu327Leu	synonymous	Exon 10 of 19	NP_005041.1	O14678
ABCD4	NM_020325.3		c.981C>A	p.Leu327Leu	synonymous	Exon 10 of 18	NP_064730.1
ABCD4	NM_001440752.1		c.981C>A	p.Leu327Leu	synonymous	Exon 10 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.981C>A	p.Leu327Leu	synonymous	Exon 10 of 19	ENSP00000349396.4	O14678
ABCD4	ENST00000460308.6	TSL:1	n.*587C>A		non_coding_transcript_exon	Exon 8 of 9	ENSP00000436527.2	E9PI46
ABCD4	ENST00000469672.5	TSL:1	n.*507C>A		non_coding_transcript_exon	Exon 7 of 9	ENSP00000434626.1	E9PPB6

Frequencies

GnomAD3 genomes

AF:

0.303

AC:

45894

AN:

151700

Hom.:

7532

Cov.:

show subpopulations

Gnomad AFR

AF:

0.169

Gnomad AMI

AF:

0.468

Gnomad AMR

AF:

0.303

Gnomad ASJ

AF:

0.443

Gnomad EAS

AF:

0.253

Gnomad SAS

AF:

0.361

Gnomad FIN

AF:

0.310

Gnomad MID

AF:

0.564

Gnomad NFE

AF:

0.370

Gnomad OTH

AF:

0.359

GnomAD2 exomes

AF:

0.324

AC:

81342

AN:

250768

AF XY:

0.338

show subpopulations

Gnomad AFR exome

AF:

0.160

Gnomad AMR exome

AF:

0.222

Gnomad ASJ exome

AF:

0.437

Gnomad EAS exome

AF:

0.242

Gnomad FIN exome

AF:

0.310

Gnomad NFE exome

AF:

0.371

Gnomad OTH exome

AF:

0.372

GnomAD4 exome

AF:

0.352

AC:

514442

AN:

1461432

Hom.:

93292

Cov.:

AF XY:

0.355

AC XY:

258297

AN XY:

726988

show subpopulations

African (AFR)

AF:

0.161

AC:

5374

AN:

33478

American (AMR)

AF:

0.230

AC:

10283

AN:

44704

Ashkenazi Jewish (ASJ)

AF:

0.444

AC:

11599

AN:

26130

East Asian (EAS)

AF:

0.242

AC:

9595

AN:

39686

South Asian (SAS)

AF:

0.371

AC:

32005

AN:

86212

European-Finnish (FIN)

AF:

0.314

AC:

16760

AN:

53360

Middle Eastern (MID)

AF:

0.524

AC:

3019

AN:

5766

European-Non Finnish (NFE)

AF:

0.364

AC:

404182

AN:

1111716

Other (OTH)

AF:

0.358

AC:

21625

AN:

60380

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

20104

40208

60311

80415

100519

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

12584

25168

37752

50336

62920

<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:

0.302

AC:

45886

AN:

151820

Hom.:

7523

Cov.:

AF XY:

0.300

AC XY:

22284

AN XY:

74202

show subpopulations

African (AFR)

AF:

0.169

AC:

6975

AN:

41388

American (AMR)

AF:

0.303

AC:

4623

AN:

15268

Ashkenazi Jewish (ASJ)

AF:

0.443

AC:

1536

AN:

3470

East Asian (EAS)

AF:

0.253

AC:

1297

AN:

5134

South Asian (SAS)

AF:

0.360

AC:

1727

AN:

4796

European-Finnish (FIN)

AF:

0.310

AC:

3277

AN:

10556

Middle Eastern (MID)

AF:

0.568

AC:

166

AN:

292

European-Non Finnish (NFE)

AF:

0.370

AC:

25103

AN:

67902

Other (OTH)

AF:

0.359

AC:

756

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1622

3243

4865

6486

8108

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

460

920

1380

1840

2300

<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:

0.355

Hom.:

23144

Bravo

AF:

0.293

Asia WGS

AF:

0.309

AC:

1072

AN:

3478

EpiCase

AF:

0.396

EpiControl

AF:

0.404

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

BayesDel_noAF

Benign

-0.47

CADD

Benign

9.1

(source)

DANN

Benign

0.75

PhyloP100

1.9

Mutation Taster

=100/0

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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