rs2066853

Positions:

• chr7-17339486-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001621.5(AHR):​c.1661G>A​(p.Arg554Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.134 in 1,613,866 control chromosomes in the GnomAD database, including 20,829 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.22 (5364 hom., cov: 32)
  • Exomes 𝑓: 0.13 (15465 hom.)
• Consequence: AHR NM_001621.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.65

Genes affected

AHR (HGNC:348): (aryl hydrocarbon receptor) The protein encoded by this gene is a ligand-activated helix-loop-helix transcription factor involved in the regulation of biological responses to planar aromatic hydrocarbons. This receptor has been shown to regulate xenobiotic-metabolizing enzymes such as cytochrome P450. Before ligand binding, the encoded protein is sequestered in the cytoplasm; upon ligand binding, this protein moves to the nucleus and stimulates transcription of target genes. [provided by RefSeq, Sep 2015]

ENSG00000283321 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0014748573).
• BP6: Variant 7-17339486-G-A is Benign according to our data. Variant chr7-17339486-G-A is described in ClinVar as [Benign]. Clinvar id is 1168239.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.447 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AHR	NM_001621.5	c.1661G>A	p.Arg554Lys	missense_variant	10/11	ENST00000242057.9	NP_001612.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AHR	ENST00000242057.9	c.1661G>A	p.Arg554Lys	missense_variant	10/11	1	NM_001621.5	ENSP00000242057.4
ENSG00000283321	ENST00000637807.1	c.1631G>A	p.Arg544Lys	missense_variant	10/12	5		ENSP00000490530.1

Frequencies

GnomAD3 genomes AF: 0.216 AC: 32840 AN: 151982 Hom.: 5335 Cov.: 32

Gnomad AFR AF: 0.452

Gnomad AMI AF: 0.0954

Gnomad AMR AF: 0.155

Gnomad ASJ AF: 0.128

Gnomad EAS AF: 0.377

Gnomad SAS AF: 0.145

Gnomad FIN AF: 0.115

Gnomad MID AF: 0.184

Gnomad NFE AF: 0.103

Gnomad OTH AF: 0.176

GnomAD3 exomes AF: 0.152 AC: 38185 AN: 250730 Hom.: 4212 AF XY: 0.144 AC XY: 19600 AN XY: 135698

Gnomad AFR exome AF: 0.458

Gnomad AMR exome AF: 0.125

Gnomad ASJ exome AF: 0.122

Gnomad EAS exome AF: 0.354

Gnomad SAS exome AF: 0.137

Gnomad FIN exome AF: 0.111

Gnomad NFE exome AF: 0.100

Gnomad OTH exome AF: 0.141

GnomAD4 exome AF: 0.126 AC: 183916 AN: 1461766 Hom.: 15465 Cov.: 33 AF XY: 0.125 AC XY: 90675 AN XY: 727188

Gnomad4 AFR exome AF: 0.460

Gnomad4 AMR exome AF: 0.133

Gnomad4 ASJ exome AF: 0.124

Gnomad4 EAS exome AF: 0.402

Gnomad4 SAS exome AF: 0.137

Gnomad4 FIN exome AF: 0.112

Gnomad4 NFE exome AF: 0.104

Gnomad4 OTH exome AF: 0.151

GnomAD4 genome AF: 0.216 AC: 32915 AN: 152100 Hom.: 5364 Cov.: 32 AF XY: 0.216 AC XY: 16058 AN XY: 74350

Gnomad4 AFR AF: 0.452

Gnomad4 AMR AF: 0.155

Gnomad4 ASJ AF: 0.128

Gnomad4 EAS AF: 0.377

Gnomad4 SAS AF: 0.145

Gnomad4 FIN AF: 0.115

Gnomad4 NFE AF: 0.103

Gnomad4 OTH AF: 0.175

Alfa AF: 0.122 Hom.: 4045

Bravo AF: 0.231

TwinsUK AF: 0.105 AC: 389

ALSPAC AF: 0.116 AC: 447

ESP6500AA AF: 0.444 AC: 1957

ESP6500EA AF: 0.101 AC: 870

ExAC AF: 0.157 AC: 18996

Asia WGS AF: 0.237 AC: 822 AN: 3478

EpiCase AF: 0.103

EpiControl AF: 0.0986

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 22, 2019	This variant is associated with the following publications: (PMID: 29185192, 10739168, 21454829, 21742528, 18818557) -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.057
BayesDel_addAF	Benign	-0.81	T
BayesDel_noAF	Benign	-0.79
CADD	Benign	4.8
DANN	Benign	0.55
DEOGEN2	Benign	0.079	.;T;.
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.025	N
LIST_S2	Benign	0.41	T;.;T
MetaRNN	Benign	0.0015	T;T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	-1.5	.;N;.
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.27	T
PROVEAN	Benign	1.2	.;N;.
REVEL	Benign	0.040
Sift	Benign	1.0	.;T;.
Sift4G	Benign	1.0	.;T;.
Polyphen		0.0	.;B;.
Vest4		0.0050
MPC		0.11
ClinPred		0.0014	T
GERP RS		0.60
Varity_R		0.035
gMVP		0.13

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: rs2066853; hg19: chr7-17379110; COSMIC: COSV54123264; COSMIC: COSV54123264;