14-74299649-A-G

Variant names:

Variant summary

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

The NM_001353593.2(ABCD4):c.-78T>C variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.347 in 1,612,364 control chromosomes in the GnomAD database, including 100,730 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.30 ( 7521 hom., cov: 32)

Exomes 𝑓: 0.35 ( 93209 hom. )

Consequence

ABCD4
NM_001353593.2 5_prime_UTR_premature_start_codon_gain

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -0.135

Publications

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

ABCD4 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 (BayesDel_noAF=-0.59).

BP6

Variant 14-74299649-A-G is Benign according to our data. Variant chr14-74299649-A-G is described in ClinVar as Benign. ClinVar VariationId is 259620.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.365 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001353593.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ABCD4	NM_005050.4	MANE Select	c.184T>C	p.Leu62Leu	synonymous	Exon 3 of 19	NP_005041.1
ABCD4	NM_001353593.2		c.-78T>C		5_prime_UTR_premature_start_codon_gain	Exon 2 of 18	NP_001340522.1
ABCD4	NM_001353594.2		c.-78T>C		5_prime_UTR_premature_start_codon_gain	Exon 2 of 16	NP_001340523.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ABCD4	ENST00000356924.9	TSL:1 MANE Select	c.184T>C	p.Leu62Leu	synonymous	Exon 3 of 19	ENSP00000349396.4
ABCD4	ENST00000469672.5	TSL:1	n.65T>C		non_coding_transcript_exon	Exon 2 of 9	ENSP00000434626.1
ABCD4	ENST00000460308.6	TSL:1	n.157+501T>C		intron	N/A	ENSP00000436527.2

Frequencies

GnomAD3 genomes

AF:

0.302

AC:

45911

AN:

151998

Hom.:

7530

Cov.:

show subpopulations

Gnomad AFR

AF:

0.168

Gnomad AMI

AF:

0.470

Gnomad AMR

AF:

0.303

Gnomad ASJ

AF:

0.443

Gnomad EAS

AF:

0.253

Gnomad SAS

AF:

0.361

Gnomad FIN

AF:

0.311

Gnomad MID

AF:

0.557

Gnomad NFE

AF:

0.369

Gnomad OTH

AF:

0.358

GnomAD2 exomes

AF:

0.325

AC:

81073

AN:

249452

AF XY:

0.338

show subpopulations

Gnomad AFR exome

AF:

0.161

Gnomad AMR exome

AF:

0.223

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:

0.373

GnomAD4 exome

AF:

0.352

AC:

514010

AN:

1460248

Hom.:

93209

Cov.:

AF XY:

0.355

AC XY:

258047

AN XY:

726364

show subpopulations

African (AFR)

AF:

0.161

AC:

5373

AN:

33460

American (AMR)

AF:

0.230

AC:

10253

AN:

44522

Ashkenazi Jewish (ASJ)

AF:

0.444

AC:

11583

AN:

26094

East Asian (EAS)

AF:

0.242

AC:

9592

AN:

39662

South Asian (SAS)

AF:

0.371

AC:

31972

AN:

86156

European-Finnish (FIN)

AF:

0.314

AC:

16759

AN:

53344

Middle Eastern (MID)

AF:

0.522

AC:

3006

AN:

5760

European-Non Finnish (NFE)

AF:

0.364

AC:

403869

AN:

1110936

Other (OTH)

AF:

0.358

AC:

21603

AN:

60314

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

15441

30881

46322

61762

77203

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

12576

25152

37728

50304

62880

<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:

45903

AN:

152116

Hom.:

7521

Cov.:

AF XY:

0.300

AC XY:

22290

AN XY:

74360

show subpopulations

African (AFR)

AF:

0.168

AC:

6978

AN:

41512

American (AMR)

AF:

0.302

AC:

4609

AN:

15260

Ashkenazi Jewish (ASJ)

AF:

0.443

AC:

1536

AN:

3468

East Asian (EAS)

AF:

0.253

AC:

1307

AN:

5176

South Asian (SAS)

AF:

0.359

AC:

1732

AN:

4818

European-Finnish (FIN)

AF:

0.311

AC:

3293

AN:

10596

Middle Eastern (MID)

AF:

0.561

AC:

165

AN:

294

European-Non Finnish (NFE)

AF:

0.369

AC:

25099

AN:

67974

Other (OTH)

AF:

0.359

AC:

756

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

1611

3222

4832

6443

8054

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:

0.352

Hom.:

17682

Bravo

AF:

0.293

Asia WGS

AF:

0.308

AC:

1069

AN:

3478

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Methylmalonic acidemia with homocystinuria, type cblJ (3)

not specified (2)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.50

BayesDel_noAF

Benign

-0.59

CADD

Benign

6.4

(source)

DANN

Benign

0.88

PhyloP100

-0.14

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

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