14-74290100-G-T

Variant names:

• chr14-74290100-G-T
• rs969369250
• NM_005050.4:c.1346C>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_005050.4(ABCD4):​c.1346C>A​(p.Thr449Lys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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. T449M) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: ABCD4 NM_005050.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.14
• Publications: 1 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.1346C>A	p.Thr449Lys	missense	Exon 13 of 19	NP_005041.1	O14678
	ABCD4	NM_020325.3		c.1346C>A	p.Thr449Lys	missense	Exon 13 of 18	NP_064730.1
	ABCD4	NM_001440752.1		c.1346C>A	p.Thr449Lys	missense	Exon 13 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.1346C>A	p.Thr449Lys	missense	Exon 13 of 19	ENSP00000349396.4	O14678
	ABCD4	ENST00000553486.5	TSL:1	n.*1047C>A		non_coding_transcript_exon	Exon 12 of 18	ENSP00000450611.1	E9PI46
	ABCD4	ENST00000553486.5	TSL:1	n.*1047C>A		3_prime_UTR	Exon 12 of 18	ENSP00000450611.1	E9PI46

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.050
CADD	Benign	18
DANN	Benign	0.95
DEOGEN2	Benign	0.15	T
Eigen	Benign	-0.29
Eigen_PC	Benign	-0.15
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.87	D
M_CAP	Uncertain	0.12	D
MetaRNN	Uncertain	0.63	D
MetaSVM	Pathogenic	1.2	D
MutationAssessor	Benign	-0.21	N
PhyloP100		4.1
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.95	N
REVEL	Uncertain	0.55
Sift	Benign	0.29	T
Sift4G	Benign	0.19	T
Polyphen		0.68	P
Vest4		0.52
MutPred		0.53		Gain of methylation at T449 (P = 0.0229)
MVP		0.91
MPC		0.31
ClinPred		0.64	D
GERP RS		4.7
PromoterAI		-0.0058	Neutral
Varity_R		0.11
gMVP		0.89
Mutation Taster		=52/48	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs969369250; hg19: chr14-74756803;