rs34453673

Variant names:

• chr5-434607-G-C
• rs34453673
• NM_001377236.1:c.1867G>C

Your query was ambiguous. Multiple possible variants found:

• chr5-434607-G-C
• chr5-434607-G-T

Variant summary

Our verdict is Benign. The variant received -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. 15/21 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
• Publications: 24 publications found

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

Our verdict: Benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001377236.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AHRR	NM_001377236.1	MANE Select	c.1867G>C	p.Asp623His	missense	Exon 11 of 11	NP_001364165.1	A0A7I2PK40
	AHRR	NM_001377239.1		c.1867G>C	p.Asp623His	missense	Exon 11 of 11	NP_001364168.1	A0A7I2PK40
	PDCD6-AHRR	NR_165159.2		n.2214G>C		non_coding_transcript_exon	Exon 14 of 14

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AHRR	ENST00000684583.1	MANE Select	c.1867G>C	p.Asp623His	missense	Exon 11 of 11	ENSP00000507476.1	A0A7I2PK40
	AHRR	ENST00000316418.10	TSL:1	c.1867G>C	p.Asp623His	missense	Exon 11 of 11	ENSP00000323816.6	A0A7I2PK40
	PDCD6-AHRR	ENST00000505113.6	TSL:1	n.*1863G>C		non_coding_transcript_exon	Exon 13 of 13	ENSP00000424601.2	A0A6Q8PH81

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

GnomAD2 exomes AF: 0.294 AC: 50016 AN: 170282 AF XY: 0.295

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 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

African (AFR) AF: 0.0545 AC: 1758 AN: 32266

American (AMR) AF: 0.274 AC: 10207 AN: 37256

Ashkenazi Jewish (ASJ) AF: 0.244 AC: 6190 AN: 25326

East Asian (EAS) AF: 0.00193 AC: 71 AN: 36796

South Asian (SAS) AF: 0.242 AC: 19575 AN: 80890

European-Finnish (FIN) AF: 0.396 AC: 19417 AN: 49028

Middle Eastern (MID) AF: 0.175 AC: 981 AN: 5606

European-Non Finnish (NFE) AF: 0.403 AC: 438361 AN: 1087038

Other (OTH) AF: 0.327 AC: 19135 AN: 58552

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

African (AFR) AF: 0.0709 AC: 2946 AN: 41564

American (AMR) AF: 0.250 AC: 3825 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.247 AC: 855 AN: 3468

East Asian (EAS) AF: 0.00521 AC: 27 AN: 5186

South Asian (SAS) AF: 0.227 AC: 1096 AN: 4828

European-Finnish (FIN) AF: 0.396 AC: 4199 AN: 10612

Middle Eastern (MID) AF: 0.122 AC: 36 AN: 294

European-Non Finnish (NFE) AF: 0.392 AC: 26668 AN: 67986

Other (OTH) AF: 0.262 AC: 553 AN: 2114

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 v4.9

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
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.0055	N
LIST_S2	Benign	0.31	T
MetaRNN	Benign	0.0010	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	-1.4	N
PhyloP100		0.67
PrimateAI	Benign	0.44	T
PROVEAN	Benign	2.3	N
REVEL	Benign	0.026
Sift	Benign	0.71	T
Sift4G	Benign	0.55	T
Polyphen		0.0	B
Vest4		0.14
MPC		0.096
ClinPred		0.0043	T
GERP RS		3.3
Varity_R		0.034
gMVP		0.19
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

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