rs4778823

Variant names:

• chr15-80570404-A-C
• rs4778823
• NM_014862.4:c.1317-3744A>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_014862.4(ARNT2):​c.1317-3744A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0841 in 152,228 control chromosomes in the GnomAD database, including 1,652 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.084 (1652 hom., cov: 33)
• Consequence: ARNT2 NM_014862.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.514
• Publications: 0 publications found

Genes affected

ARNT2 (HGNC:16876): (aryl hydrocarbon receptor nuclear translocator 2) This gene encodes a member of the basic-helix-loop-helix-Per-Arnt-Sim (bHLH-PAS) superfamily of transcription factors. The encoded protein acts as a partner for several sensor proteins of the bHLH-PAS family, forming heterodimers with the sensor proteins that bind regulatory DNA sequences in genes responsive to developmental and environmental stimuli. Under hypoxic conditions, the encoded protein complexes with hypoxia-inducible factor 1alpha in the nucleus and this complex binds to hypoxia-responsive elements in enhancers and promoters of oxygen-responsive genes. A highly similar protein in mouse forms functional complexes with both aryl hydrocarbon receptors and Single-minded proteins, suggesting additional roles for the encoded protein in the metabolism of xenobiotic compounds and the regulation of neurogenesis, respectively. [provided by RefSeq, Dec 2013]

ARNT2 Gene-Disease associations (from GenCC):

• Webb-Dattani syndrome

  Inheritance: AR Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P
• septooptic dysplasia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.99).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.274 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARNT2	NM_014862.4	c.1317-3744A>C		intron_variant	Intron 12 of 18	ENST00000303329.9	NP_055677.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARNT2	ENST00000303329.9	c.1317-3744A>C		intron_variant	Intron 12 of 18	1	NM_014862.4	ENSP00000307479.4
ARNT2	ENST00000527771.5	c.1284-3744A>C		intron_variant	Intron 12 of 18	2		ENSP00000453792.1
ARNT2	ENST00000533983.5	c.1284-3744A>C		intron_variant	Intron 13 of 19	5		ENSP00000453651.1
ARNT2	ENST00000558849.1	n.535-3744A>C		intron_variant	Intron 4 of 4	4

Frequencies

GnomAD3 genomes AF: 0.0838 AC: 12749 AN: 152112 Hom.: 1643 Cov.: 33

Gnomad AFR AF: 0.279

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0568

Gnomad ASJ AF: 0.00519

Gnomad EAS AF: 0.0146

Gnomad SAS AF: 0.00290

Gnomad FIN AF: 0.00160

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00123

Gnomad OTH AF: 0.0697

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0841 AC: 12797 AN: 152228 Hom.: 1652 Cov.: 33 AF XY: 0.0819 AC XY: 6097 AN XY: 74426

African (AFR) AF: 0.279 AC: 11562 AN: 41482

American (AMR) AF: 0.0568 AC: 868 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00519 AC: 18 AN: 3470

East Asian (EAS) AF: 0.0148 AC: 77 AN: 5188

South Asian (SAS) AF: 0.00290 AC: 14 AN: 4826

European-Finnish (FIN) AF: 0.00160 AC: 17 AN: 10624

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00123 AC: 84 AN: 68024

Other (OTH) AF: 0.0733 AC: 155 AN: 2116

Alfa AF: 0.0548 Hom.: 159

Bravo AF: 0.0981

Asia WGS AF: 0.0420 AC: 148 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.99
CADD	Benign	1.3
DANN	Benign	0.45
PhyloP100		-0.51
Mutation Taster		=100/0	polymorphism (auto)

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: rs4778823; hg19: chr15-80862745;