Variant 5-423895-C-T details in Genebe, Genetics Data Aggregator

Variant summary

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

The NM_001377236.1(AHRR):c.626C>T(p.Thr209Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000498 in 1,604,844 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00024 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000030 ( 0 hom. )

Consequence

AHRR
NM_001377236.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.0960

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:):

PDCD6-AHRR links:

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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=0.01609698).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
AHRR	NM_001377236.1 linkuse as main transcript	c.626C>T	p.Thr209Met	missense_variant	7/11	ENST00000684583.1
PDCD6-AHRR	NR_165159.2 linkuse as main transcript	n.919C>T		non_coding_transcript_exon_variant	9/14
AHRR	NM_001377239.1 linkuse as main transcript	c.626C>T	p.Thr209Met	missense_variant	7/11
PDCD6-AHRR	NR_165163.2 linkuse as main transcript	n.919C>T		non_coding_transcript_exon_variant	9/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
AHRR	ENST00000684583.1 linkuse as main transcript	c.626C>T	p.Thr209Met	missense_variant	7/11		NM_001377236.1	P1
AHRR	ENST00000316418.10 linkuse as main transcript	c.626C>T	p.Thr209Met	missense_variant	7/11	1		P1
AHRR	ENST00000506456.1 linkuse as main transcript	c.206C>T	p.Thr69Met	missense_variant	3/7	2
AHRR	ENST00000510910.1 linkuse as main transcript	n.537C>T		non_coding_transcript_exon_variant	2/2	4

Frequencies

GnomAD3 genomes

AF:

0.000243

AC:

AN:

152248

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00183

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:

0.0000588

Gnomad OTH

AF:

0.00191

GnomAD3 exomes

AF:

0.0000455

AC:

AN:

241660

Hom.:

AF XY:

0.0000455

AC XY:

AN XY:

131840

show subpopulations

Gnomad AFR exome

AF:

0.0000650

Gnomad AMR exome

AF:

0.0000870

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000559

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000668

Gnomad NFE exome

AF:

0.0000445

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000296

AC:

AN:

1452478

Hom.:

Cov.:

AF XY:

0.0000263

AC XY:

AN XY:

722840

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.000291

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000226

Gnomad4 NFE exome

AF:

0.0000162

Gnomad4 OTH exome

AF:

0.000133

GnomAD4 genome

AF:

0.000243

AC:

AN:

152366

Hom.:

Cov.:

AF XY:

0.000242

AC XY:

AN XY:

74498

show subpopulations

Gnomad4 AFR

AF:

0.0000240

Gnomad4 AMR

AF:

0.00183

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00189

Alfa

AF:

0.000142

Hom.:

Bravo

AF:

0.000434

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000119

AC:

ExAC

AF:

0.0000496

AC:

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 submitter

clinical testing

Ambry Genetics

Jun 11, 2024

The c.638C>T (p.T213M) alteration is located in exon 7 (coding exon 7) of the AHRR gene. This alteration results from a C to T substitution at nucleotide position 638, causing the threonine (T) at amino acid position 213 to be replaced by a methionine (M). 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

0.066

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.65

CADD

Benign

2.8

DANN

Benign

0.89

DEOGEN2

Benign

0.044

T;.;T;T

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.020

LIST_S2

Benign

0.39

T;T;T;T

M_CAP

Benign

0.0055

MetaRNN

Benign

0.016

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.42

N;N;.;.

MutationTaster

Benign

1.0

N;N;N;N

PrimateAI

Uncertain

0.51

PROVEAN

Benign

0.25

N;N;N;N

REVEL

Benign

0.0070

Sift

Benign

0.12

T;T;T;T

Sift4G

Benign

0.092

.;.;T;T

Polyphen

0.027

B;B;.;B

Vest4

0.10

MVP

0.18

MPC

0.61

ClinPred

0.0097

GERP RS

-0.019

Varity_R

0.058

gMVP

0.16

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over