5-422777-C-T

Variant names:

• chr5-422777-C-T
• rs1736192384
• NM_001377236.1:c.490C>T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001377236.1(AHRR):​c.490C>T​(p.Arg164Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,872 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: AHRR NM_001377236.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.32

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:54724): (PDCD6-AHRR readthrough (NMD candidate)) Predicted to enable calcium ion binding activity. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.87

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AHRR	NM_001377236.1	c.490C>T	p.Arg164Cys	missense_variant	Exon 6 of 11	ENST00000684583.1	NP_001364165.1
AHRR	NM_001377239.1	c.490C>T	p.Arg164Cys	missense_variant	Exon 6 of 11		NP_001364168.1
PDCD6-AHRR	NR_165159.2	n.783C>T		non_coding_transcript_exon_variant	Exon 8 of 14
PDCD6-AHRR	NR_165163.2	n.783C>T		non_coding_transcript_exon_variant	Exon 8 of 13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AHRR	ENST00000684583.1	c.490C>T	p.Arg164Cys	missense_variant	Exon 6 of 11		NM_001377236.1	ENSP00000507476.1
PDCD6-AHRR	ENST00000675395.1	n.*486C>T		non_coding_transcript_exon_variant	Exon 8 of 14			ENSP00000502570.1
PDCD6-AHRR	ENST00000675395.1	n.*486C>T		3_prime_UTR_variant	Exon 8 of 14			ENSP00000502570.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461872 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 727238

Gnomad4 AFR exome AF: 0.0000299

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 07, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.502C>T (p.R168C) alteration is located in exon 6 (coding exon 6) of the AHRR gene. This alteration results from a C to T substitution at nucleotide position 502, causing the arginine (R) at amino acid position 168 to be replaced by a cysteine (C). 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	Pathogenic	0.68
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.15
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.65	D;.;T;T
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.95	D;D;D;D
M_CAP	Benign	0.027	D
MetaRNN	Pathogenic	0.87	D;D;D;D
MetaSVM	Uncertain	-0.12	T
MutationAssessor	Pathogenic	3.0	M;M;.;.
PrimateAI	Pathogenic	0.80	T
PROVEAN	Pathogenic	-6.8	D;D;D;D
REVEL	Uncertain	0.55
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Pathogenic	0.0	.;.;D;D
Polyphen		1.0	D;D;.;D
Vest4		0.87
MutPred		0.69		Loss of loop (P = 0.2237);Loss of loop (P = 0.2237);.;.;
MVP		0.81
MPC		1.8
ClinPred		1.0	D
GERP RS		4.8
Varity_R		0.87
gMVP		0.86

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: rs1736192384; hg19: chr5-422892; COSMIC: COSV57091197; COSMIC: COSV57091197;