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GeneBe

5-422833-T-G

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Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001377236.1(AHRR):ā€‹c.546T>Gā€‹(p.Phe182Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,518 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: not found (cov: 32)
Exomes š‘“: 0.0000027 ( 0 hom. )

Consequence

AHRR
NM_001377236.1 missense

Scores

18

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.483
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]

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.040949553).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
AHRRNM_001377236.1 linkuse as main transcriptc.546T>G p.Phe182Leu missense_variant 6/11 ENST00000684583.1
PDCD6-AHRRNR_165159.2 linkuse as main transcriptn.839T>G non_coding_transcript_exon_variant 8/14
AHRRNM_001377239.1 linkuse as main transcriptc.546T>G p.Phe182Leu missense_variant 6/11
PDCD6-AHRRNR_165163.2 linkuse as main transcriptn.839T>G non_coding_transcript_exon_variant 8/13

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
AHRRENST00000684583.1 linkuse as main transcriptc.546T>G p.Phe182Leu missense_variant 6/11 NM_001377236.1 P1
AHRRENST00000316418.10 linkuse as main transcriptc.546T>G p.Phe182Leu missense_variant 6/111 P1
AHRRENST00000506456.1 linkuse as main transcriptc.126T>G p.Phe42Leu missense_variant 2/72
AHRRENST00000510910.1 linkuse as main transcriptn.457T>G non_coding_transcript_exon_variant 1/24

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.0000121
AC:
3
AN:
248944
Hom.:
0
AF XY:
0.00000740
AC XY:
1
AN XY:
135102
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000266
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000274
AC:
4
AN:
1461518
Hom.:
0
Cov.:
30
AF XY:
0.00000413
AC XY:
3
AN XY:
727014
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000360
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32
Alfa
AF:
0.0000282
Hom.:
0
Bravo
AF:
0.0000151
ExAC
AF:
0.0000165
AC:
2
EpiCase
AF:
0.0000545
EpiControl
AF:
0.000119

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsNov 30, 2022The c.558T>G (p.F186L) alteration is located in exon 6 (coding exon 6) of the AHRR gene. This alteration results from a T to G substitution at nucleotide position 558, causing the phenylalanine (F) at amino acid position 186 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.30
BayesDel_addAF
Benign
-0.34
T
BayesDel_noAF
Benign
-0.66
CADD
Benign
0.053
DANN
Benign
0.60
DEOGEN2
Benign
0.061
T;.;T;T
Eigen
Benign
-1.7
Eigen_PC
Benign
-1.8
FATHMM_MKL
Benign
0.099
N
LIST_S2
Benign
0.22
T;T;T;T
M_CAP
Benign
0.0020
T
MetaRNN
Benign
0.041
T;T;T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
-0.69
N;N;.;.
MutationTaster
Benign
1.0
N;N;N;N
PrimateAI
Benign
0.44
T
PROVEAN
Benign
-0.57
N;N;N;N
REVEL
Benign
0.022
Sift
Benign
0.69
T;T;T;T
Polyphen
0.15
B;B;.;B
Vest4
0.054
MutPred
0.33
Gain of relative solvent accessibility (P = 0.0098);Gain of relative solvent accessibility (P = 0.0098);.;.;
MVP
0.099
MPC
0.68
ClinPred
0.024
T
GERP RS
-9.2
Varity_R
0.032
gMVP
0.29

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

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

Other links and lift over

dbSNP: rs758866636; hg19: chr5-422948; API