rs2066853

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. Synonymous variant affecting the same amino acid position (i.e. R554R) has been classified as Likely benign.

• 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]

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	UniProt
AHR	NM_001621.5	c.1661G>A	p.Arg554Lys	missense_variant	10/11	ENST00000242057.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AHR	ENST00000242057.9	c.1661G>A	p.Arg554Lys	missense_variant	10/11	1	NM_001621.5	P2
AHR	ENST00000463496.1	c.1661G>A	p.Arg554Lys	missense_variant, NMD_transcript_variant	10/12	1
AHR	ENST00000642825.1	c.1616G>A	p.Arg539Lys	missense_variant	14/15			A2
AHR	ENST00000492120.1	n.643G>A		non_coding_transcript_exon_variant	2/2	2

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	Invitae	Jan 31, 2024	- -
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) -

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
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
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.27	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;