rs2228099

Variant names:

• chr1-150836413-C-G
• rs2228099
• NM_001668.4:c.567G>C

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Moderate BP7 BA1

The NM_001668.4(ARNT):​c.567G>C​(p.Val189Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.388 in 1,613,580 control chromosomes in the GnomAD database, including 124,120 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 0.42 (13711 hom., cov: 32)
  • Exomes 𝑓: 0.38 (110409 hom.)
• Consequence: ARNT NM_001668.4 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.305
• Publications: 77 publications found

Genes affected

ARNT (HGNC:700): (aryl hydrocarbon receptor nuclear translocator) This gene encodes a protein containing a basic helix-loop-helix domain and two characteristic PAS domains along with a PAC domain. The encoded protein binds to ligand-bound aryl hydrocarbon receptor and aids in the movement of this complex to the nucleus, where it promotes the expression of genes involved in xenobiotic metabolism. This protein is also a co-factor for transcriptional regulation by hypoxia-inducible factor 1. Chromosomal translocation of this locus with the ETV6 (ets variant 6) gene on chromosome 12 have been described in leukemias. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Oct 2013]

ACMG classification

Our verdict: Benign. The variant received -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.42).
• BP7: Synonymous conserved (PhyloP=0.305 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.525 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001668.4. 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
	ARNT	NM_001668.4	MANE Select	c.567G>C	p.Val189Val	synonymous	Exon 7 of 22	NP_001659.1	P27540-1
	ARNT	NM_001350225.2		c.564G>C	p.Val188Val	synonymous	Exon 7 of 22	NP_001337154.1
	ARNT	NM_001286036.2		c.567G>C	p.Val189Val	synonymous	Exon 7 of 22	NP_001272965.1	P27540-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARNT	ENST00000358595.10	TSL:1 MANE Select	c.567G>C	p.Val189Val	synonymous	Exon 7 of 22	ENSP00000351407.5	P27540-1
	ARNT	ENST00000354396.6	TSL:1	c.567G>C	p.Val189Val	synonymous	Exon 7 of 22	ENSP00000346372.2	P27540-4
	ARNT	ENST00000515192.5	TSL:1	c.540G>C	p.Val180Val	synonymous	Exon 8 of 23	ENSP00000423851.1	P27540-3

Frequencies

GnomAD3 genomes AF: 0.418 AC: 63496 AN: 151856 Hom.: 13700 Cov.: 32

Gnomad AFR AF: 0.500

Gnomad AMI AF: 0.265

Gnomad AMR AF: 0.441

Gnomad ASJ AF: 0.476

Gnomad EAS AF: 0.387

Gnomad SAS AF: 0.544

Gnomad FIN AF: 0.344

Gnomad MID AF: 0.440

Gnomad NFE AF: 0.367

Gnomad OTH AF: 0.413

GnomAD2 exomes AF: 0.407 AC: 101998 AN: 250672 AF XY: 0.412

Gnomad AFR exome AF: 0.505

Gnomad AMR exome AF: 0.424

Gnomad ASJ exome AF: 0.465

Gnomad EAS exome AF: 0.368

Gnomad FIN exome AF: 0.350

Gnomad NFE exome AF: 0.366

Gnomad OTH exome AF: 0.396

GnomAD4 exome AF: 0.385 AC: 562627 AN: 1461606 Hom.: 110409 Cov.: 47 AF XY: 0.389 AC XY: 282972 AN XY: 727100

African (AFR) AF: 0.508 AC: 17023 AN: 33480

American (AMR) AF: 0.423 AC: 18879 AN: 44680

Ashkenazi Jewish (ASJ) AF: 0.470 AC: 12280 AN: 26134

East Asian (EAS) AF: 0.379 AC: 15042 AN: 39684

South Asian (SAS) AF: 0.535 AC: 46144 AN: 86232

European-Finnish (FIN) AF: 0.351 AC: 18739 AN: 53388

Middle Eastern (MID) AF: 0.458 AC: 2643 AN: 5766

European-Non Finnish (NFE) AF: 0.366 AC: 407362 AN: 1111862

Other (OTH) AF: 0.406 AC: 24515 AN: 60380

GnomAD4 genome AF: 0.418 AC: 63534 AN: 151974 Hom.: 13711 Cov.: 32 AF XY: 0.421 AC XY: 31294 AN XY: 74276

African (AFR) AF: 0.500 AC: 20712 AN: 41438

American (AMR) AF: 0.440 AC: 6723 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.476 AC: 1653 AN: 3470

East Asian (EAS) AF: 0.387 AC: 2001 AN: 5174

South Asian (SAS) AF: 0.543 AC: 2616 AN: 4820

European-Finnish (FIN) AF: 0.344 AC: 3629 AN: 10546

Middle Eastern (MID) AF: 0.429 AC: 126 AN: 294

European-Non Finnish (NFE) AF: 0.367 AC: 24954 AN: 67944

Other (OTH) AF: 0.416 AC: 879 AN: 2114

Alfa AF: 0.387 Hom.: 4027

Bravo AF: 0.422

Asia WGS AF: 0.428 AC: 1486 AN: 3478

EpiCase AF: 0.372

EpiControl AF: 0.379

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.42
CADD	Benign	6.2
DANN	Benign	0.76
PhyloP100		0.30
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
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: rs2228099; hg19: chr1-150808889; COSMIC: COSV62229502; COSMIC: COSV62229502;