5-376612-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001377236.1(AHRR):c.247G>A(p.Val83Met) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000413 in 1,112,638 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. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000042 (0 hom., cov: 0)
  • Exomes 𝑓: 0.000041 (0 hom.)
• Consequence: AHRR NM_001377236.1 missense, splice_region
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.112

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.10897261).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AHRR	NM_001377236.1	c.247G>A	p.Val83Met	missense_variant, splice_region_variant	4/11	ENST00000684583.1
PDCD6-AHRR	NR_165159.2	n.540G>A		splice_region_variant, non_coding_transcript_exon_variant	6/14
AHRR	NM_001377239.1	c.247G>A	p.Val83Met	missense_variant, splice_region_variant	4/11
PDCD6-AHRR	NR_165163.2	n.540G>A		splice_region_variant, non_coding_transcript_exon_variant	6/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AHRR	ENST00000684583.1	c.247G>A	p.Val83Met	missense_variant, splice_region_variant	4/11		NM_001377236.1	P1
AHRR	ENST00000316418.10	c.247G>A	p.Val83Met	missense_variant, splice_region_variant	4/11	1		P1
AHRR	ENST00000510400.5	c.247G>A	p.Val83Met	missense_variant, splice_region_variant	4/6	4
AHRR	ENST00000514523.1	c.-204G>A		splice_region_variant, 5_prime_UTR_variant	4/6	4

Frequencies

GnomAD3 genomes AF: 0.0000418 AC: 1 AN: 23914 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.00

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: 0.000171

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000322 AC: 7 AN: 217656 Hom.: 0 AF XY: 0.0000168 AC XY: 2 AN XY: 118946

Gnomad AFR exome AF: 0.0000724

Gnomad AMR exome AF: 0.0000335

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000673

Gnomad SAS exome AF: 0.000114

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000989

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000413 AC: 45 AN: 1088724 Hom.: 0 Cov.: 36 AF XY: 0.0000414 AC XY: 22 AN XY: 531792

Gnomad4 AFR exome AF: 0.0000772

Gnomad4 AMR exome AF: 0.0000383

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000190

Gnomad4 SAS exome AF: 0.000410

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000134

Gnomad4 OTH exome AF: 0.0000514

GnomAD4 genome AF: 0.0000418 AC: 1 AN: 23914 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 11716

Gnomad4 AFR AF: 0.00

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: 0.000171

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000113

ExAC AF: 0.00000827 AC: 1

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

Sep 14, 2022

The c.259G>A (p.V87M) alteration is located in exon 4 (coding exon 4) of the AHRR gene. This alteration results from a G to A substitution at nucleotide position 259, causing the valine (V) at amino acid position 87 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	0.12
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.56
Cadd	Benign	11
Dann	Benign	0.97
DEOGEN2	Benign	0.093	T;.;.
Eigen	Benign	-0.56
Eigen_PC	Benign	-0.75
FATHMM_MKL	Benign	0.096	N
LIST_S2	Benign	0.81	T;T;T
M_CAP	Benign	0.0041	T
MetaRNN	Benign	0.11	T;T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	0.69	N;N;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-0.99	N;N;N
REVEL	Benign	0.070
Sift	Uncertain	0.017	D;D;T
Polyphen		0.95	P;D;.
Vest4		0.22
MVP		0.65
MPC		1.2
ClinPred		0.041	T
GERP RS		-0.35
Varity_R		0.23
gMVP		0.31

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

Other links and lift over

dbSNP: rs201403478; hg19: chr5-376727;