5-376640-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001377236.1(AHRR):c.275C>T(p.Ala92Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000538 in 1,096,078 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 0.00039 (0 hom., cov: 0)
  • Exomes 𝑓: 0.000048 (0 hom.)
• Consequence: AHRR NM_001377236.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -2.12

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]

PDCD6-AHRR (HGNC:):

ACMG classification

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=0.024982512).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AHRR	NM_001377236.1	c.275C>T	p.Ala92Val	missense_variant	4/11	ENST00000684583.1
PDCD6-AHRR	NR_165159.2	n.568C>T		non_coding_transcript_exon_variant	6/14
AHRR	NM_001377239.1	c.275C>T	p.Ala92Val	missense_variant	4/11
PDCD6-AHRR	NR_165163.2	n.568C>T		non_coding_transcript_exon_variant	6/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AHRR	ENST00000684583.1	c.275C>T	p.Ala92Val	missense_variant	4/11		NM_001377236.1	P1
AHRR	ENST00000316418.10	c.275C>T	p.Ala92Val	missense_variant	4/11	1		P1
AHRR	ENST00000510400.5	c.275C>T	p.Ala92Val	missense_variant	4/6	4
AHRR	ENST00000514523.1	c.-176C>T		5_prime_UTR_variant	4/6	4

Frequencies

GnomAD3 genomes AF: 0.000393 AC: 7 AN: 17808 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.000386

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: 0.000814

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000437 AC: 10 AN: 229036 Hom.: 0 AF XY: 0.0000479 AC XY: 6 AN XY: 125138

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: 0.0000708

Gnomad FIN exome AF: 0.000209

Gnomad NFE exome AF: 0.0000385

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000482 AC: 52 AN: 1078270 Hom.: 0 Cov.: 36 AF XY: 0.0000455 AC XY: 24 AN XY: 527120

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000520

Gnomad4 SAS exome AF: 0.0000603

Gnomad4 FIN exome AF: 0.000162

Gnomad4 NFE exome AF: 0.0000492

Gnomad4 OTH exome AF: 0.0000263

GnomAD4 genome AF: 0.000393 AC: 7 AN: 17808 Hom.: 0 Cov.: 0 AF XY: 0.000230 AC XY: 2 AN XY: 8684

Gnomad4 AFR AF: 0.000386

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: 0.000814

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000462 Hom.: 0

Bravo AF: 0.0000227

ExAC AF: 0.0000331 AC: 4

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 13, 2021

The c.287C>T (p.A96V) alteration is located in exon 4 (coding exon 4) of the AHRR gene. This alteration results from a C to T substitution at nucleotide position 287, causing the alanine (A) at amino acid position 96 to be replaced by a valine (V). 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	0.076
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.66
Cadd	Benign	0.32
Dann	Benign	0.68
DEOGEN2	Benign	0.077	T;.;.
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.0087	N
LIST_S2	Benign	0.38	T;T;T
M_CAP	Benign	0.0017	T
MetaRNN	Benign	0.025	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.14	N;N;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-1.6	N;N;N
REVEL	Benign	0.013
Sift	Benign	0.35	T;T;T
Polyphen		0.0030	B;B;.
Vest4		0.068
MutPred		0.20		Loss of relative solvent accessibility (P = 0.0676);Loss of relative solvent accessibility (P = 0.0676);.;
MVP		0.16
MPC		0.59
ClinPred		0.017	T
GERP RS		-2.0
Varity_R		0.084
gMVP		0.24

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs754366584; hg19: chr5-376755; COSMIC: COSV57082165;