Genetic Variant AHRR:p.Asp623Tyr (chr5-434607-G-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001377236.1(AHRR):c.1867G>T(p.Asp623Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000283 in 1,412,898 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 34)

Exomes 𝑓: 0.0000028 ( 0 hom. )

Consequence

AHRR
NM_001377236.1 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.667

Publications

0 publications found

Variant links:

Genes affected

AHRR (HGNC:346): (aryl hydrocarbon receptor repressor) The protein encoded by this gene participates in the aryl hydrocarbon receptor (AhR) signaling cascade, which mediates dioxin toxicity, and is involved in regulation of cell growth and differentiation. It functions as a feedback modulator by repressing AhR-dependent gene expression. Alternatively spliced transcript variants encoding different isoforms have been described for this gene. [provided by RefSeq, Jun 2011]

AHRR links:

PDCD6-AHRR (HGNC:54724): (PDCD6-AHRR readthrough (NMD candidate)) Predicted to enable calcium ion binding activity. [provided by Alliance of Genome Resources, Apr 2022]

PDCD6-AHRR links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.057283938).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
AHRR	NM_001377236.1 link	c.1867G>T	p.Asp623Tyr	missense_variant	Exon 11 of 11	ENST00000684583.1	NP_001364165.1
AHRR	NM_001377239.1 link	c.1867G>T	p.Asp623Tyr	missense_variant	Exon 11 of 11		NP_001364168.1
PDCD6-AHRR	NR_165159.2 link	n.2214G>T		non_coding_transcript_exon_variant	Exon 14 of 14
PDCD6-AHRR	NR_165163.2 link	n.2160G>T		non_coding_transcript_exon_variant	Exon 13 of 13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
AHRR	ENST00000684583.1 link	c.1867G>T	p.Asp623Tyr	missense_variant	Exon 11 of 11	NM_001377236.1	ENSP00000507476.1
PDCD6-AHRR	ENST00000675395.1 link	n.*1917G>T		non_coding_transcript_exon_variant	Exon 14 of 14		ENSP00000502570.1
PDCD6-AHRR	ENST00000675395.1 link	n.*1917G>T		3_prime_UTR_variant	Exon 14 of 14		ENSP00000502570.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000283

AC:

AN:

1412898

Hom.:

Cov.:

100

AF XY:

0.00000429

AC XY:

AN XY:

698538

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32266

American (AMR)

AF:

0.00

AC:

AN:

37270

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25326

East Asian (EAS)

AF:

0.00

AC:

AN:

36802

South Asian (SAS)

AF:

0.00

AC:

AN:

80898

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49054

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5606

European-Non Finnish (NFE)

AF:

0.00000368

AC:

AN:

1087116

Other (OTH)

AF:

0.00

AC:

AN:

58560

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.513

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.078

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.61

CADD

Benign

5.8

(source)

DANN

Benign

0.40

DEOGEN2

Benign

0.050

T;.;T;T

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.077

LIST_S2

Benign

0.51

T;T;T;T

M_CAP

Benign

0.0014

MetaRNN

Benign

0.057

T;T;T;T

MetaSVM

Benign

-0.96

MutationAssessor

Benign

0.0

N;.;.;.

PhyloP100

0.67

PrimateAI

Benign

0.44

PROVEAN

Benign

1.1

N;N;N;N

REVEL

Benign

0.029

Sift

Benign

0.20

T;T;T;T

Sift4G

Pathogenic

0.0

.;.;T;T

Vest4

0.17

ClinPred

0.046

GERP RS

3.3

Varity_R

0.054

gMVP

0.23

Mutation Taster

=99/1

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over