5-376675-C-G

Variant summary

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

The NM_001377236.1(AHRR):c.310C>G(p.Leu104Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000529 in 1,610,710 control chromosomes in the GnomAD database, including 1 homozygotes. 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L104P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00030 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00055 (1 hom.)
• Consequence: AHRR NM_001377236.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.40

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=0.025810242).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AHRR	NM_001377236.1	c.310C>G	p.Leu104Val	missense_variant	4/11	ENST00000684583.1
PDCD6-AHRR	NR_165159.2	n.603C>G		non_coding_transcript_exon_variant	6/14
AHRR	NM_001377239.1	c.310C>G	p.Leu104Val	missense_variant	4/11
PDCD6-AHRR	NR_165163.2	n.603C>G		non_coding_transcript_exon_variant	6/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AHRR	ENST00000684583.1	c.310C>G	p.Leu104Val	missense_variant	4/11		NM_001377236.1	P1
AHRR	ENST00000316418.10	c.310C>G	p.Leu104Val	missense_variant	4/11	1		P1
AHRR	ENST00000510400.5	c.310C>G	p.Leu104Val	missense_variant	4/6	4
AHRR	ENST00000514523.1	c.-141C>G		5_prime_UTR_variant	4/6	4

Frequencies

GnomAD3 genomes AF: 0.000302 AC: 46 AN: 152232 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000724

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: 0.000617

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000300 AC: 72 AN: 239728 Hom.: 0 AF XY: 0.000283 AC XY: 37 AN XY: 130522

Gnomad AFR exome AF: 0.000207

Gnomad AMR exome AF: 0.0000295

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: 0.000624

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000553 AC: 806 AN: 1458478 Hom.: 1 Cov.: 34 AF XY: 0.000525 AC XY: 381 AN XY: 725168

Gnomad4 AFR exome AF: 0.000150

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000117

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000703

Gnomad4 OTH exome AF: 0.000315

GnomAD4 genome AF: 0.000302 AC: 46 AN: 152232 Hom.: 0 Cov.: 33 AF XY: 0.000202 AC XY: 15 AN XY: 74368

Gnomad4 AFR AF: 0.0000724

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: 0.000617

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.000660 Hom.: 0

Bravo AF: 0.000321

ESP6500AA AF: 0.000234 AC: 1

ESP6500EA AF: 0.000354 AC: 3

ExAC AF: 0.000339 AC: 41

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

Mar 08, 2024

The c.322C>G (p.L108V) alteration is located in exon 4 (coding exon 4) of the AHRR gene. This alteration results from a C to G substitution at nucleotide position 322, causing the leucine (L) at amino acid position 108 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	0.064
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.72
Cadd	Benign	0.013
Dann	Benign	0.31
DEOGEN2	Benign	0.053	T;.;.
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.024	N
LIST_S2	Benign	0.35	T;T;T
M_CAP	Benign	0.0023	T
MetaRNN	Benign	0.026	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N;N;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-0.12	N;N;N
REVEL	Benign	0.0
Sift	Benign	0.52	T;T;T
Polyphen		0.029	B;B;.
Vest4		0.084
MVP		0.30
MPC		0.63
ClinPred		0.0040	T
GERP RS		-2.9
Varity_R		0.073
gMVP		0.12

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: rs201010505; hg19: chr5-376790;