15-80404523-C-A

Position:

• chr15-80404523-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_014862.4(ARNT2):​c.8C>A​(p.Thr3Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000149 in 1,076,030 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000015 (0 hom.)
• Consequence: ARNT2 NM_014862.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.73

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.20640177).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ARNT2	NM_014862.4	c.8C>A	p.Thr3Asn	missense_variant	1/19	ENST00000303329.9	NP_055677.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ARNT2	ENST00000303329.9	c.8C>A	p.Thr3Asn	missense_variant	1/19	1	NM_014862.4	ENSP00000307479	P1
ARNT2	ENST00000529181.1	n.174C>A		non_coding_transcript_exon_variant	1/5	1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000149 AC: 16 AN: 1076030 Hom.: 0 Cov.: 30 AF XY: 0.00000946 AC XY: 5 AN XY: 528492

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000178

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 01, 2022

The c.8C>A (p.T3N) alteration is located in exon 1 (coding exon 1) of the ARNT2 gene. This alteration results from a C to A substitution at nucleotide position 8, causing the threonine (T) at amino acid position 3 to be replaced by an asparagine (N). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.49
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.57
CADD	Uncertain	24
DANN	Benign	0.97
DEOGEN2	Benign	0.14	T;.
Eigen	Benign	-0.14
Eigen_PC	Benign	-0.094
FATHMM_MKL	Benign	0.63	D
LIST_S2	Benign	0.84	T;T
M_CAP	Pathogenic	0.40	D
MetaRNN	Benign	0.21	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.9	L;.
MutationTaster	Benign	0.51	N
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-0.34	N;.
REVEL	Benign	0.057
Sift	Uncertain	0.0040	D;.
Sift4G	Uncertain	0.024	D;D
Polyphen		0.53	P;.
Vest4		0.23
MutPred		0.11		Loss of glycosylation at T3 (P = 0.0021);Loss of glycosylation at T3 (P = 0.0021);
MVP		0.19
MPC		1.5
ClinPred		0.64	D
GERP RS		2.7
Varity_R		0.18
gMVP		0.33

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

Publications

LitVar

Other links and lift over

dbSNP: rs1218717224; hg19: chr15-80696865;