rs17782508

Variant names:

• chr14-74303138-C-T
• rs17782508
• ENST00000557177.1:c.-202C>T

Variant summary

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

The ENST00000557177.1(VRTN):​c.-202C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.326 in 439,878 control chromosomes in the GnomAD database, including 24,968 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.30 (7257 hom., cov: 33)
  • Exomes 𝑓: 0.34 (17711 hom.)
• Consequence: VRTN ENST00000557177.1 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.26
• Publications: 6 publications found

Genes affected

VRTN (HGNC:20223): (vertebrae development associated) Predicted to enable sequence-specific DNA binding activity and transposase activity. Predicted to be involved in regulation of transcription by RNA polymerase II. Predicted to be active in chromatin. [provided by Alliance of Genome Resources, Apr 2022]

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

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 14-74303138-C-T is Benign according to our data. Variant chr14-74303138-C-T is described in ClinVar as Benign. ClinVar VariationId is 1181620.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.358 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000557177.1. 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.-226G>A		upstream_gene	N/A	NP_005041.1	O14678
	ABCD4	NM_020325.3		c.-226G>A		upstream_gene	N/A	NP_064730.1
	ABCD4	NM_001440752.1		c.-226G>A		upstream_gene	N/A	NP_001427681.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VRTN	ENST00000557177.1	TSL:4	c.-202C>T		5_prime_UTR	Exon 1 of 3	ENSP00000452158.1	G3V537
	ABCD4	ENST00000356924.9	TSL:1 MANE Select	c.-226G>A		upstream_gene	N/A	ENSP00000349396.4	O14678
	ABCD4	ENST00000460308.6	TSL:1	n.-226G>A		upstream_gene	N/A	ENSP00000436527.2	E9PI46

Frequencies

GnomAD3 genomes AF: 0.296 AC: 45080 AN: 152098 Hom.: 7265 Cov.: 33

Gnomad AFR AF: 0.167

Gnomad AMI AF: 0.467

Gnomad AMR AF: 0.300

Gnomad ASJ AF: 0.425

Gnomad EAS AF: 0.251

Gnomad SAS AF: 0.360

Gnomad FIN AF: 0.292

Gnomad MID AF: 0.554

Gnomad NFE AF: 0.362

Gnomad OTH AF: 0.355

GnomAD4 exome AF: 0.342 AC: 98460 AN: 287662 Hom.: 17711 Cov.: 3 AF XY: 0.345 AC XY: 50917 AN XY: 147536

African (AFR) AF: 0.168 AC: 1255 AN: 7476

American (AMR) AF: 0.256 AC: 1981 AN: 7744

Ashkenazi Jewish (ASJ) AF: 0.433 AC: 4248 AN: 9818

East Asian (EAS) AF: 0.239 AC: 5500 AN: 23058

South Asian (SAS) AF: 0.361 AC: 4093 AN: 11350

European-Finnish (FIN) AF: 0.294 AC: 8603 AN: 29304

Middle Eastern (MID) AF: 0.509 AC: 912 AN: 1792

European-Non Finnish (NFE) AF: 0.366 AC: 65558 AN: 179012

Other (OTH) AF: 0.348 AC: 6310 AN: 18108

GnomAD4 genome AF: 0.296 AC: 45072 AN: 152216 Hom.: 7257 Cov.: 33 AF XY: 0.294 AC XY: 21868 AN XY: 74420

African (AFR) AF: 0.167 AC: 6947 AN: 41574

American (AMR) AF: 0.299 AC: 4574 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.425 AC: 1476 AN: 3470

East Asian (EAS) AF: 0.251 AC: 1297 AN: 5174

South Asian (SAS) AF: 0.359 AC: 1732 AN: 4822

European-Finnish (FIN) AF: 0.292 AC: 3089 AN: 10588

Middle Eastern (MID) AF: 0.562 AC: 164 AN: 292

European-Non Finnish (NFE) AF: 0.362 AC: 24617 AN: 67980

Other (OTH) AF: 0.356 AC: 752 AN: 2114

Alfa AF: 0.294 Hom.: 1050

Bravo AF: 0.288

Asia WGS AF: 0.306 AC: 1062 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	2.5
DANN	Benign	0.82
PhyloP100		-1.3
PromoterAI		0.14	Neutral
Mutation Taster		=100/0	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs17782508;

hg19: chr14-74769841;