chr14-74292356-G-C

Variant names:

• chr14-74292356-G-C
• rs35073715
• NM_005050.4:c.1049C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_005050.4(ABCD4):​c.1049C>G​(p.Thr350Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0241 in 1,614,040 control chromosomes in the GnomAD database, including 555 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. T350M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.019 (37 hom., cov: 33)
  • Exomes 𝑓: 0.025 (518 hom.)
• Consequence: ABCD4 NM_005050.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 3.61
• Publications: 9 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=0.006796807).
• BP6: Variant 14-74292356-G-C is Benign according to our data. Variant chr14-74292356-G-C is described in ClinVar as Benign. ClinVar VariationId is 380512.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0187 (2847/152310) while in subpopulation NFE AF = 0.0272 (1853/68046). AF 95% confidence interval is 0.0262. There are 37 homozygotes in GnomAd4. There are 1358 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 37 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCD4	NM_005050.4	MANE Select	c.1049C>G	p.Thr350Arg	missense	Exon 11 of 19	NP_005041.1	O14678
	ABCD4	NM_020325.3		c.1049C>G	p.Thr350Arg	missense	Exon 11 of 18	NP_064730.1
	ABCD4	NM_001440752.1		c.1049C>G	p.Thr350Arg	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.1049C>G	p.Thr350Arg	missense	Exon 11 of 19	ENSP00000349396.4	O14678
	ABCD4	ENST00000460308.6	TSL:1	n.*655C>G		non_coding_transcript_exon	Exon 9 of 9	ENSP00000436527.2	E9PI46
	ABCD4	ENST00000469672.5	TSL:1	n.*575C>G		non_coding_transcript_exon	Exon 8 of 9	ENSP00000434626.1	E9PPB6

Frequencies

GnomAD3 genomes AF: 0.0187 AC: 2848 AN: 152192 Hom.: 37 Cov.: 33

Gnomad AFR AF: 0.00613

Gnomad AMI AF: 0.0307

Gnomad AMR AF: 0.0271

Gnomad ASJ AF: 0.0202

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.0171

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0272

Gnomad OTH AF: 0.0192

GnomAD2 exomes AF: 0.0180 AC: 4514 AN: 251224 AF XY: 0.0175

Gnomad AFR exome AF: 0.00511

Gnomad AMR exome AF: 0.0171

Gnomad ASJ exome AF: 0.0244

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0165

Gnomad NFE exome AF: 0.0272

Gnomad OTH exome AF: 0.0214

GnomAD4 exome AF: 0.0247 AC: 36069 AN: 1461730 Hom.: 518 Cov.: 34 AF XY: 0.0239 AC XY: 17394 AN XY: 727158

African (AFR) AF: 0.00358 AC: 120 AN: 33478

American (AMR) AF: 0.0173 AC: 774 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0222 AC: 581 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000591 AC: 51 AN: 86258

European-Finnish (FIN) AF: 0.0159 AC: 849 AN: 53316

Middle Eastern (MID) AF: 0.00971 AC: 56 AN: 5768

European-Non Finnish (NFE) AF: 0.0290 AC: 32236 AN: 1111954

Other (OTH) AF: 0.0232 AC: 1402 AN: 60396

GnomAD4 genome AF: 0.0187 AC: 2847 AN: 152310 Hom.: 37 Cov.: 33 AF XY: 0.0182 AC XY: 1358 AN XY: 74462

African (AFR) AF: 0.00611 AC: 254 AN: 41568

American (AMR) AF: 0.0270 AC: 413 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.0202 AC: 70 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00124 AC: 6 AN: 4824

European-Finnish (FIN) AF: 0.0171 AC: 182 AN: 10616

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0272 AC: 1853 AN: 68046

Other (OTH) AF: 0.0190 AC: 40 AN: 2110

Alfa AF: 0.0227 Hom.: 43

Bravo AF: 0.0190

ESP6500AA AF: 0.00658 AC: 29

ESP6500EA AF: 0.0263 AC: 226

ExAC AF: 0.0175 AC: 2124

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.0298

EpiControl AF: 0.0287

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Methylmalonic acidemia with homocystinuria, type cblJ (2)
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Uncertain	-0.050
CADD	Benign	20
DANN	Uncertain	0.98
DEOGEN2	Benign	0.062	T
Eigen	Benign	0.11
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.85	D
MetaRNN	Benign	0.0068	T
MetaSVM	Uncertain	0.19	D
MutationAssessor	Benign	2.0	M
PhyloP100		3.6
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-1.1	N
REVEL	Uncertain	0.34
Sift	Benign	0.18	T
Sift4G	Benign	0.33	T
Polyphen		0.10	B
Vest4		0.097
MPC		0.29
ClinPred		0.011	T
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.26
gMVP		0.86
Mutation Taster		=92/8	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs35073715; hg19: chr14-74759059;