rs4986826

chr7-17339533-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.1708G>A(p.Val570Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00553 in 1,614,096 control chromosomes in the GnomAD database, including 229 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V570A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.021 (115 hom., cov: 32)
  • Exomes 𝑓: 0.0039 (114 hom.)
• Consequence: AHR NM_001621.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.49

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=0.0021272004).
• BP6: Variant 7-17339533-G-A is Benign according to our data. Variant chr7-17339533-G-A is described in ClinVar as [Benign]. Clinvar id is 780672.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0658 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AHR	NM_001621.5	c.1708G>A	p.Val570Ile	missense_variant	10/11	ENST00000242057.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AHR	ENST00000242057.9	c.1708G>A	p.Val570Ile	missense_variant	10/11	1	NM_001621.5	P2
AHR	ENST00000463496.1	c.1708G>A	p.Val570Ile	missense_variant, NMD_transcript_variant	10/12	1
AHR	ENST00000642825.1	c.1663G>A	p.Val555Ile	missense_variant	14/15			A2
AHR	ENST00000492120.1			downstream_gene_variant		2

Frequencies

GnomAD3 genomes AF: 0.0213 AC: 3247 AN: 152156 Hom.: 113 Cov.: 32

Gnomad AFR AF: 0.0676

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0128

Gnomad ASJ AF: 0.00893

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0791

Gnomad NFE AF: 0.00220

Gnomad OTH AF: 0.0186

GnomAD3 exomes AF: 0.00779 AC: 1956 AN: 251078 Hom.: 37 AF XY: 0.00649 AC XY: 881 AN XY: 135762

Gnomad AFR exome AF: 0.0701

Gnomad AMR exome AF: 0.0101

Gnomad ASJ exome AF: 0.00913

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.00144

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00247

Gnomad OTH exome AF: 0.00898

GnomAD4 exome AF: 0.00388 AC: 5670 AN: 1461822 Hom.: 114 Cov.: 32 AF XY: 0.00366 AC XY: 2665 AN XY: 727200

Gnomad4 AFR exome AF: 0.0709

Gnomad4 AMR exome AF: 0.0109

Gnomad4 ASJ exome AF: 0.0103

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00152

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.00148

Gnomad4 OTH exome AF: 0.00892

GnomAD4 genome AF: 0.0214 AC: 3264 AN: 152274 Hom.: 115 Cov.: 32 AF XY: 0.0208 AC XY: 1546 AN XY: 74462

Gnomad4 AFR AF: 0.0679

Gnomad4 AMR AF: 0.0127

Gnomad4 ASJ AF: 0.00893

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00220

Gnomad4 OTH AF: 0.0184

Alfa AF: 0.00615 Hom.: 35

Bravo AF: 0.0241

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.0647 AC: 285

ESP6500EA AF: 0.00198 AC: 17

ExAC AF: 0.00867 AC: 1052

Asia WGS AF: 0.00520 AC: 18 AN: 3478

EpiCase AF: 0.00387

EpiControl AF: 0.00421

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 30, 2024

- -

AHR-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 17, 2020

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.69
Cadd	Benign	13
Dann	Benign	0.85
Eigen	Benign	-0.15
Eigen_PC	Benign	-0.093
FATHMM_MKL	Benign	0.65	D
LIST_S2	Benign	0.80	T;.;T
MetaRNN	Benign	0.0021	T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.26	T
Polyphen		0.30	.;B;.
Vest4		0.028
MVP		0.38
MPC		0.090
ClinPred		0.0089	T
GERP RS		3.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.029
gMVP		0.12

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: rs4986826; hg19: chr7-17379157; COSMIC: COSV54123274; COSMIC: COSV54123274;