15-80404523-C-G

Variant names:

• chr15-80404523-C-G
• rs1218717224
• NM_014862.4:c.8C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_014862.4(ARNT2):​c.8C>G​(p.Thr3Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000929 in 1,076,030 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T3N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 9.3e-7 (0 hom.)
• Consequence: ARNT2 NM_014862.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.73
• 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-DT (HGNC:56077): (ARNT2 divergent transcript)

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15567908).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014862.4. 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
	ARNT2	NM_014862.4	MANE Select	c.8C>G	p.Thr3Ser	missense	Exon 1 of 19	NP_055677.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARNT2	ENST00000303329.9	TSL:1 MANE Select	c.8C>G	p.Thr3Ser	missense	Exon 1 of 19	ENSP00000307479.4	Q9HBZ2-1
	ARNT2	ENST00000529181.1	TSL:1	n.174C>G		non_coding_transcript_exon	Exon 1 of 5
	ARNT2	ENST00000869656.1		c.8C>G	p.Thr3Ser	missense	Exon 1 of 20	ENSP00000539715.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 9.29e-7 AC: 1 AN: 1076030 Hom.: 0 Cov.: 30 AF XY: 0.00000189 AC XY: 1 AN XY: 528492

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 20670

American (AMR) AF: 0.00 AC: 0 AN: 17810

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14248

East Asian (EAS) AF: 0.00 AC: 0 AN: 10602

South Asian (SAS) AF: 0.0000177 AC: 1 AN: 56620

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 16702

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3266

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 897434

Other (OTH) AF: 0.00 AC: 0 AN: 38678

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.33
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.57
CADD	Uncertain	24
DANN	Benign	0.93
DEOGEN2	Benign	0.12	T
Eigen	Benign	-0.26
Eigen_PC	Benign	-0.18
FATHMM_MKL	Benign	0.63	D
LIST_S2	Benign	0.76	T
M_CAP	Pathogenic	0.39	D
MetaRNN	Benign	0.16	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.9	L
PhyloP100		1.7
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-0.090	N
REVEL	Benign	0.088
Sift	Uncertain	0.020	D
Sift4G	Benign	0.098	T
Polyphen		0.10	B
Vest4		0.15
MutPred		0.093		Loss of glycosylation at T3 (P = 0.1691)
MVP		0.23
MPC		1.1
ClinPred		0.26	T
GERP RS		2.7
PromoterAI		-0.13	Neutral
Varity_R		0.16
gMVP		0.16

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: rs1218717224; hg19: chr15-80696865;