chr14-74303274-G-A

Variant names:

• chr14-74303274-G-A
• rs67772080
• ENST00000557177.1:c.-164+98G>A

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.-164+98G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.311 in 208,518 control chromosomes in the GnomAD database, including 10,900 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.30 (7255 hom., cov: 33)
  • Exomes 𝑓: 0.35 (3645 hom.)
• Consequence: VRTN ENST00000557177.1 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.586
• Publications: 1 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: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics, Orphanet, ClinGen

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BP6: Variant 14-74303274-G-A is Benign according to our data. Variant chr14-74303274-G-A is described in ClinVar as Benign. ClinVar VariationId is 1234864.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
There are no transcript annotations for this variant.

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VRTN	ENST00000557177.1	TSL:4	c.-164+98G>A		intron	N/A	ENSP00000452158.1	G3V537
	ABCD4	ENST00000460308.6	TSL:1	n.-362C>T		upstream_gene	N/A	ENSP00000436527.2	E9PI46
	ABCD4	ENST00000948604.1		c.-362C>T		upstream_gene	N/A	ENSP00000618663.1

Frequencies

GnomAD3 genomes AF: 0.296 AC: 45087 AN: 152082 Hom.: 7263 Cov.: 33

Gnomad AFR AF: 0.167

Gnomad AMI AF: 0.471

Gnomad AMR AF: 0.300

Gnomad ASJ AF: 0.425

Gnomad EAS AF: 0.252

Gnomad SAS AF: 0.360

Gnomad FIN AF: 0.292

Gnomad MID AF: 0.557

Gnomad NFE AF: 0.362

Gnomad OTH AF: 0.354

GnomAD4 exome AF: 0.350 AC: 19689 AN: 56318 Hom.: 3645 AF XY: 0.349 AC XY: 9855 AN XY: 28244

African (AFR) AF: 0.164 AC: 374 AN: 2282

American (AMR) AF: 0.271 AC: 424 AN: 1564

Ashkenazi Jewish (ASJ) AF: 0.428 AC: 1048 AN: 2450

East Asian (EAS) AF: 0.230 AC: 1047 AN: 4558

South Asian (SAS) AF: 0.363 AC: 222 AN: 612

European-Finnish (FIN) AF: 0.304 AC: 914 AN: 3008

Middle Eastern (MID) AF: 0.547 AC: 173 AN: 316

European-Non Finnish (NFE) AF: 0.375 AC: 14028 AN: 37438

Other (OTH) AF: 0.357 AC: 1459 AN: 4090

GnomAD4 genome AF: 0.296 AC: 45079 AN: 152200 Hom.: 7255 Cov.: 33 AF XY: 0.294 AC XY: 21868 AN XY: 74398

African (AFR) AF: 0.167 AC: 6936 AN: 41538

American (AMR) AF: 0.299 AC: 4575 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.425 AC: 1476 AN: 3472

East Asian (EAS) AF: 0.252 AC: 1303 AN: 5176

South Asian (SAS) AF: 0.359 AC: 1733 AN: 4826

European-Finnish (FIN) AF: 0.292 AC: 3093 AN: 10590

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

European-Non Finnish (NFE) AF: 0.362 AC: 24623 AN: 67998

Other (OTH) AF: 0.354 AC: 747 AN: 2108

Alfa AF: 0.294 Hom.: 1048

Bravo AF: 0.288

Asia WGS AF: 0.307 AC: 1065 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	-0.95
CADD	Benign	3.9
DANN	Benign	0.58
PhyloP100		0.59
PromoterAI		-0.024	Neutral

Splicing

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

Other links and lift over

dbSNP: rs67772080; hg19: chr14-74769977;