dbSNP rs530894063: AHR:p.Thr22Pro (chr7-17299328-A-C) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_001621.5(AHR):c.64A>C(p.Thr22Pro) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000657 in 152,200 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Consequence

AHR
NM_001621.5 missense, splice_region

Scores

Splicing: ADA: 0.9903

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.70

Variant links:

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]

AHR links:

ENSG00000283321 (HGNC:):

ENSG00000283321 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AHR	NM_001621.5 link	c.64A>C	p.Thr22Pro	missense_variant, splice_region_variant	Exon 1 of 11	ENST00000242057.9	NP_001612.1	P35869A0A024R9Z8
LOC101927609	XR_007060234.1 link	n.-8T>G		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AHR	ENST00000242057.9 link	c.64A>C	p.Thr22Pro	missense_variant, splice_region_variant	Exon 1 of 11	1	NM_001621.5	ENSP00000242057.4		P35869
ENSG00000283321	ENST00000637807.1 link	c.34A>C	p.Thr12Pro	missense_variant, splice_region_variant	Exon 1 of 12	5		ENSP00000490530.1		A0A1B0GVI7

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152200

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152200

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74352

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.010

BayesDel_noAF

Benign

-0.25

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Benign

0.30

T;.

Eigen

Uncertain

0.22

Eigen_PC

Uncertain

0.30

FATHMM_MKL

Benign

0.43

LIST_S2

Benign

0.78

.;T

M_CAP

Benign

0.076

MetaRNN

Benign

0.26

T;T

MetaSVM

Benign

-0.98

MutationAssessor

Benign

1.8

L;.

PrimateAI

Uncertain

0.69

PROVEAN

Uncertain

-2.4

N;.

REVEL

Benign

0.077

Sift

Benign

0.043

D;.

Sift4G

Benign

0.082

T;.

Polyphen

0.73

P;.

Vest4

0.18

MutPred

0.24

Loss of phosphorylation at T22 (P = 0.0335);.;

MVP

0.38

MPC

0.31

ClinPred

0.91

GERP RS

4.8

Varity_R

0.59

gMVP

0.46

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

0.99

dbscSNV1_RF

Pathogenic

0.86

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over