chr5-353743-G-C

Position:

• chr5-353743-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001377236.1(AHRR):​c.76G>C​(p.Gly26Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000891 in 1,458,282 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000089 (0 hom.)
• Consequence: AHRR NM_001377236.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.56

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.38598493).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AHRR	NM_001377236.1	c.76G>C	p.Gly26Arg	missense_variant	3/11	ENST00000684583.1
PDCD6-AHRR	NR_165159.2	n.369G>C		non_coding_transcript_exon_variant	5/14
AHRR	NM_001377239.1	c.76G>C	p.Gly26Arg	missense_variant	3/11
PDCD6-AHRR	NR_165163.2	n.369G>C		non_coding_transcript_exon_variant	5/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AHRR	ENST00000684583.1	c.76G>C	p.Gly26Arg	missense_variant	3/11		NM_001377236.1	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000891 AC: 13 AN: 1458282 Hom.: 0 Cov.: 31 AF XY: 0.0000110 AC XY: 8 AN XY: 725524

Gnomad4 AFR exome AF: 0.00

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: 0.0000117

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000472 Hom.: 0

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

May 21, 2024

The c.88G>C (p.G30R) alteration is located in exon 3 (coding exon 3) of the AHRR gene. This alteration results from a G to C substitution at nucleotide position 88, causing the glycine (G) at amino acid position 30 to be replaced by an arginine (R). 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	0.23
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.39
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.22	T;.;.;.;.
Eigen	Uncertain	0.29
Eigen_PC	Benign	0.18
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.67	T;T;T;T;T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.39	T;T;T;T;T
MetaSVM	Benign	-0.81	T
MutationAssessor	Benign	0.28	N;N;.;.;.
MutationTaster	Benign	0.98	D;D;D;D
PrimateAI	Uncertain	0.64	T
PROVEAN	Uncertain	-3.4	D;D;D;D;D
REVEL	Benign	0.21
Sift	Uncertain	0.0070	D;D;D;T;T
Sift4G	Benign	0.078	.;.;T;T;T
Polyphen		1.0	D;D;.;.;.
Vest4		0.40
MutPred		0.26		Loss of loop (P = 0.0203);Loss of loop (P = 0.0203);.;.;.;
MVP		0.65
MPC		1.7
ClinPred		0.91	D
GERP RS		4.5
Varity_R		0.22
gMVP		0.49

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: rs1742942209; hg19: chr5-353858;