rs3742801

Variant names:

• chr14-74292303-C-T
• rs3742801
• NM_005050.4:c.1102G>A

Your query was ambiguous. Multiple possible variants found:

• chr14-74292303-C-T
• chr14-74292303-C-A
• chr14-74292303-C-G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_005050.4(ABCD4):​c.1102G>A​(p.Glu368Lys) 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 1,613,546 control chromosomes in the GnomAD database, including 101,224 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.31 (7716 hom., cov: 32)
  • Exomes 𝑓: 0.35 (93508 hom.)
• Consequence: ABCD4 NM_005050.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.0780
• Publications: 60 publications found

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

ENSG00000258559 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.0028183162).
• BP6: Variant 14-74292303-C-T is Benign according to our data. Variant chr14-74292303-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 259619.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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCD4	NM_005050.4	MANE Select	c.1102G>A	p.Glu368Lys	missense	Exon 11 of 19	NP_005041.1	O14678
	ABCD4	NM_020325.3		c.1102G>A	p.Glu368Lys	missense	Exon 11 of 18	NP_064730.1
	ABCD4	NM_001440752.1		c.1102G>A	p.Glu368Lys	missense	Exon 11 of 18	NP_001427681.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCD4	ENST00000356924.9	TSL:1 MANE Select	c.1102G>A	p.Glu368Lys	missense	Exon 11 of 19	ENSP00000349396.4	O14678
	ABCD4	ENST00000469672.5	TSL:1	n.*628G>A		non_coding_transcript_exon	Exon 8 of 9	ENSP00000434626.1	E9PPB6
	ABCD4	ENST00000553486.5	TSL:1	n.*803G>A		non_coding_transcript_exon	Exon 10 of 18	ENSP00000450611.1	E9PI46

Frequencies

GnomAD3 genomes AF: 0.309 AC: 46891 AN: 151916 Hom.: 7725 Cov.: 32

Gnomad AFR AF: 0.191

Gnomad AMI AF: 0.467

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: 0.363

GnomAD2 exomes AF: 0.327 AC: 82082 AN: 251102 AF XY: 0.340

Gnomad AFR exome AF: 0.186

Gnomad AMR exome AF: 0.224

Gnomad ASJ exome AF: 0.437

Gnomad EAS exome AF: 0.242

Gnomad FIN exome AF: 0.310

Gnomad NFE exome AF: 0.372

Gnomad OTH exome AF: 0.372

GnomAD4 exome AF: 0.353 AC: 515495 AN: 1461512 Hom.: 93508 Cov.: 43 AF XY: 0.356 AC XY: 258752 AN XY: 727074

African (AFR) AF: 0.185 AC: 6185 AN: 33478

American (AMR) AF: 0.231 AC: 10346 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.444 AC: 11600 AN: 26132

East Asian (EAS) AF: 0.242 AC: 9600 AN: 39698

South Asian (SAS) AF: 0.371 AC: 31985 AN: 86250

European-Finnish (FIN) AF: 0.314 AC: 16726 AN: 53276

Middle Eastern (MID) AF: 0.526 AC: 3033 AN: 5768

European-Non Finnish (NFE) AF: 0.364 AC: 404294 AN: 1111804

Other (OTH) AF: 0.360 AC: 21726 AN: 60388

GnomAD4 genome AF: 0.308 AC: 46888 AN: 152034 Hom.: 7716 Cov.: 32 AF XY: 0.306 AC XY: 22751 AN XY: 74306

African (AFR) AF: 0.191 AC: 7915 AN: 41502

American (AMR) AF: 0.305 AC: 4664 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.442 AC: 1535 AN: 3470

East Asian (EAS) AF: 0.251 AC: 1293 AN: 5158

South Asian (SAS) AF: 0.359 AC: 1730 AN: 4814

European-Finnish (FIN) AF: 0.311 AC: 3278 AN: 10554

Middle Eastern (MID) AF: 0.565 AC: 166 AN: 294

European-Non Finnish (NFE) AF: 0.370 AC: 25118 AN: 67962

Other (OTH) AF: 0.364 AC: 766 AN: 2106

Alfa AF: 0.356 Hom.: 47867

Bravo AF: 0.300

TwinsUK AF: 0.366 AC: 1356

ALSPAC AF: 0.354 AC: 1365

ESP6500AA AF: 0.197 AC: 868

ESP6500EA AF: 0.364 AC: 3128

ExAC AF: 0.327 AC: 39739

Asia WGS AF: 0.311 AC: 1078 AN: 3478

EpiCase AF: 0.396

EpiControl AF: 0.404

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	Methylmalonic acidemia with homocystinuria, type cblJ (2)
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.13
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Benign	0.052	T
Eigen	Benign	-0.89
Eigen_PC	Benign	-0.77
FATHMM_MKL	Benign	0.066	N
LIST_S2	Benign	0.85	T
MetaRNN	Benign	0.0028	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.0	L
PhyloP100		0.078
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.66	N
REVEL	Uncertain	0.32
Sift	Benign	0.23	T
Sift4G	Benign	0.52	T
Polyphen		0.0020	B
Vest4		0.042
MPC		0.27
ClinPred		0.0080	T
GERP RS		1.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.043
gMVP		0.74
Mutation Taster		=96/4	polymorphism (auto)

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

Other links and lift over

dbSNP: rs3742801; hg19: chr14-74759006; COSMIC: COSV53991476; COSMIC: COSV53991476;