rs34453673

Positions:

• chr5-434607-G-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001377236.1(AHRR):​c.1867G>C​(p.Asp623His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.355 in 1,565,030 control chromosomes in the GnomAD database, including 108,152 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.27 (7067 hom., cov: 34)
  • Exomes 𝑓: 0.37 (101085 hom.)
• Consequence: AHRR NM_001377236.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.667

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 Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0010014772).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.388 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AHRR	NM_001377236.1	c.1867G>C	p.Asp623His	missense_variant	11/11	ENST00000684583.1	NP_001364165.1
PDCD6-AHRR	NR_165159.2	n.2214G>C		non_coding_transcript_exon_variant	14/14
AHRR	NM_001377239.1	c.1867G>C	p.Asp623His	missense_variant	11/11		NP_001364168.1
PDCD6-AHRR	NR_165163.2	n.2160G>C		non_coding_transcript_exon_variant	13/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AHRR	ENST00000684583.1	c.1867G>C	p.Asp623His	missense_variant	11/11		NM_001377236.1	ENSP00000507476	P1
AHRR	ENST00000316418.10	c.1867G>C	p.Asp623His	missense_variant	11/11	1		ENSP00000323816	P1
AHRR	ENST00000506456.1	c.1447G>C	p.Asp483His	missense_variant	7/7	2		ENSP00000426932
AHRR	ENST00000507048.1	n.1678G>C		non_coding_transcript_exon_variant	2/2	2

Frequencies

GnomAD3 genomes AF: 0.267 AC: 40635 AN: 152154 Hom.: 7067 Cov.: 34

Gnomad AFR AF: 0.0711

Gnomad AMI AF: 0.475

Gnomad AMR AF: 0.250

Gnomad ASJ AF: 0.247

Gnomad EAS AF: 0.00519

Gnomad SAS AF: 0.225

Gnomad FIN AF: 0.396

Gnomad MID AF: 0.117

Gnomad NFE AF: 0.392

Gnomad OTH AF: 0.263

GnomAD3 exomes AF: 0.294 AC: 50016 AN: 170282 Hom.: 8514 AF XY: 0.295 AC XY: 27018 AN XY: 91562

Gnomad AFR exome AF: 0.0622

Gnomad AMR exome AF: 0.278

Gnomad ASJ exome AF: 0.249

Gnomad EAS exome AF: 0.00388

Gnomad SAS exome AF: 0.236

Gnomad FIN exome AF: 0.394

Gnomad NFE exome AF: 0.385

Gnomad OTH exome AF: 0.282

GnomAD4 exome AF: 0.365 AC: 515695 AN: 1412758 Hom.: 101085 Cov.: 100 AF XY: 0.362 AC XY: 252632 AN XY: 698454

Gnomad4 AFR exome AF: 0.0545

Gnomad4 AMR exome AF: 0.274

Gnomad4 ASJ exome AF: 0.244

Gnomad4 EAS exome AF: 0.00193

Gnomad4 SAS exome AF: 0.242

Gnomad4 FIN exome AF: 0.396

Gnomad4 NFE exome AF: 0.403

Gnomad4 OTH exome AF: 0.327

GnomAD4 genome AF: 0.267 AC: 40638 AN: 152272 Hom.: 7067 Cov.: 34 AF XY: 0.263 AC XY: 19606 AN XY: 74472

Gnomad4 AFR AF: 0.0709

Gnomad4 AMR AF: 0.250

Gnomad4 ASJ AF: 0.247

Gnomad4 EAS AF: 0.00521

Gnomad4 SAS AF: 0.227

Gnomad4 FIN AF: 0.396

Gnomad4 NFE AF: 0.392

Gnomad4 OTH AF: 0.262

Alfa AF: 0.344 Hom.: 3101

Bravo AF: 0.247

TwinsUK AF: 0.414 AC: 1535

ALSPAC AF: 0.411 AC: 1583

ESP6500AA AF: 0.0714 AC: 288

ESP6500EA AF: 0.364 AC: 3041

ExAC AF: 0.236 AC: 27100

Asia WGS AF: 0.100 AC: 349 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.78	T
BayesDel_noAF	Benign	-0.74
CADD	Benign	2.6
DANN	Benign	0.069
DEOGEN2	Benign	0.042	T;.;T;T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.0055	N
LIST_S2	Benign	0.31	T;T;T;T
MetaRNN	Benign	0.0010	T;T;T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	-1.4	N;.;.;.
MutationTaster	Benign	1.0	P;P;P;P
PrimateAI	Benign	0.44	T
PROVEAN	Benign	2.3	N;N;N;N
REVEL	Benign	0.026
Sift	Benign	0.71	T;T;T;T
Sift4G	Benign	0.55	.;.;T;T
Polyphen		0.0	B;B;.;B
Vest4		0.14
MPC		0.096
ClinPred		0.0043	T
GERP RS		3.3
Varity_R		0.034
gMVP		0.19

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: rs34453673; hg19: chr5-434722; COSMIC: COSV57092619; COSMIC: COSV57092619;