dbSNP rs147795328: ABCD4:p.Arg348Trp (chr14-74292363-G-A) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_005050.4(ABCD4):c.1042C>T(p.Arg348Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00138 in 1,614,070 control chromosomes in the GnomAD database, including 37 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R348L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00092 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0014 ( 35 hom. )

Consequence

ABCD4
NM_005050.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 3.09

Publications

4 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: Orphanet, Labcorp Genetics (formerly Invitae), ClinGen, G2P, Ambry Genetics

ABCD4 links:

ENSG00000258559 (HGNC:):

ENSG00000258559 links:

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript NM_005050.4, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (MetaRNN=0.0085271895).

BP6

Variant 14-74292363-G-A is Benign according to our data. Variant chr14-74292363-G-A is described in ClinVar as Benign. ClinVar VariationId is 389017.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000919 (140/152296) while in subpopulation SAS AF = 0.016 (77/4818). AF 95% confidence interval is 0.0131. There are 2 homozygotes in GnomAd4. There are 94 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

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.1042C>T	p.Arg348Trp	missense	Exon 11 of 19	NP_005041.1	O14678
ABCD4	NM_020325.3		c.1042C>T	p.Arg348Trp	missense	Exon 11 of 18	NP_064730.1
ABCD4	NM_001440752.1		c.1042C>T	p.Arg348Trp	missense	Exon 11 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.1042C>T	p.Arg348Trp	missense	Exon 11 of 19	ENSP00000349396.4	O14678
ABCD4	ENST00000460308.6	TSL:1	n.*648C>T		non_coding_transcript_exon	Exon 9 of 9	ENSP00000436527.2	E9PI46
ABCD4	ENST00000469672.5	TSL:1	n.*568C>T		non_coding_transcript_exon	Exon 8 of 9	ENSP00000434626.1	E9PPB6

Frequencies

GnomAD3 genomes

AF:

0.000927

AC:

141

AN:

152178

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000507

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000589

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.0162

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000412

Gnomad OTH

AF:

0.00144

GnomAD2 exomes

AF:

0.00256

AC:

644

AN:

251188

AF XY:

0.00348

show subpopulations

Gnomad AFR exome

AF:

0.000554

Gnomad AMR exome

AF:

0.000347

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000590

Gnomad OTH exome

AF:

0.000653

GnomAD4 exome

AF:

0.00143

AC:

2094

AN:

1461774

Hom.:

Cov.:

AF XY:

0.00196

AC XY:

1425

AN XY:

727188

show subpopulations

African (AFR)

AF:

0.000478

AC:

AN:

33480

American (AMR)

AF:

0.000380

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0175

AC:

1511

AN:

86256

European-Finnish (FIN)

AF:

0.0000563

AC:

AN:

53310

Middle Eastern (MID)

AF:

0.00589

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000363

AC:

404

AN:

1112004

Other (OTH)

AF:

0.00179

AC:

108

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

127

254

381

508

635

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

128

160

<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:

0.000919

AC:

140

AN:

152296

Hom.:

Cov.:

AF XY:

0.00126

AC XY:

AN XY:

74456

show subpopulations

African (AFR)

AF:

0.000505

AC:

AN:

41568

American (AMR)

AF:

0.000588

AC:

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.000386

AC:

AN:

5184

South Asian (SAS)

AF:

0.0160

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000412

AC:

AN:

68032

Other (OTH)

AF:

0.00142

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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:

0.000707

Hom.:

Bravo

AF:

0.000582

Asia WGS

AF:

0.00433

AC:

AN:

3478

EpiCase

AF:

0.000981

EpiControl

AF:

0.000711

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

ABCD4-related disorder (1)

Methylmalonic acidemia with homocystinuria, type cblJ (1)

not provided (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Uncertain

-0.060

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.058

Eigen

Benign

-0.046

Eigen_PC

Benign

0.050

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.85

MetaRNN

Benign

0.0085

MetaSVM

Uncertain

0.15

MutationAssessor

Benign

1.1

PhyloP100

3.1

PrimateAI

Benign

0.23

PROVEAN

Benign

-0.68

REVEL

Uncertain

0.41

Sift

Benign

0.19

Sift4G

Uncertain

0.025

Varity_R

0.12

gMVP

0.76

Mutation Taster

=94/6

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

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