14-74292303-C-G

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_005050.4(ABCD4):​c.1102G>C​(p.Glu368Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E368K) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ABCD4 NM_005050.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0780
• Publications: 0 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: ClinGen, Labcorp Genetics (formerly Invitae), G2P, Orphanet, Ambry Genetics

ENSG00000258559 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.062289327).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCD4	NM_005050.4	c.1102G>C	p.Glu368Gln	missense_variant	Exon 11 of 19	ENST00000356924.9	NP_005041.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ABCD4	ENST00000356924.9	c.1102G>C	p.Glu368Gln	missense_variant	Exon 11 of 19	1	NM_005050.4	ENSP00000349396.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 43

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.0018	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	14
DANN	Benign	0.91
DEOGEN2	Benign	0.039	T
Eigen	Benign	-0.85
Eigen_PC	Benign	-0.74
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.68	T
M_CAP	Benign	0.043	D
MetaRNN	Benign	0.062	T
MetaSVM	Benign	-0.40	T
MutationAssessor	Benign	0.81	L
PhyloP100		0.078
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.17	N
REVEL	Benign	0.19
Sift	Benign	0.51	T
Sift4G	Benign	0.48	T
Polyphen		0.0070	B
Vest4		0.060
MutPred		0.30		Gain of loop (P = 0.0851);
MVP		0.75
MPC		0.25
ClinPred		0.063	T
GERP RS		1.5
Varity_R		0.049
gMVP		0.70
Mutation Taster		=96/4	polymorphism

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;