5-434607-G-C

Variant names:

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

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. 15/22 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: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.

Transcripts

RefSeq

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

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AHRR	ENST00000684583.1	c.1867G>C	p.Asp623His	missense_variant	Exon 11 of 11		NM_001377236.1	ENSP00000507476.1
PDCD6-AHRR	ENST00000675395.1	n.*1917G>C		non_coding_transcript_exon_variant	Exon 14 of 14			ENSP00000502570.1
PDCD6-AHRR	ENST00000675395.1	n.*1917G>C		3_prime_UTR_variant	Exon 14 of 14			ENSP00000502570.1

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

Gnomad4 AFR exome AF: 0.0545 AC: 1758 AN: 32266

Gnomad4 AMR exome AF: 0.274 AC: 10207 AN: 37256

Gnomad4 ASJ exome AF: 0.244 AC: 6190 AN: 25326

Gnomad4 EAS exome AF: 0.00193 AC: 71 AN: 36796

Gnomad4 SAS exome AF: 0.242 AC: 19575 AN: 80890

Gnomad4 FIN exome AF: 0.396 AC: 19417 AN: 49028

Gnomad4 NFE exome AF: 0.403 AC: 438361 AN: 1087038

Gnomad4 Remaining exome 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

Gnomad4 AFR AF: 0.0709 AC: 0.0708786 AN: 0.0708786

Gnomad4 AMR AF: 0.250 AC: 0.249869 AN: 0.249869

Gnomad4 ASJ AF: 0.247 AC: 0.24654 AN: 0.24654

Gnomad4 EAS AF: 0.00521 AC: 0.00520632 AN: 0.00520632

Gnomad4 SAS AF: 0.227 AC: 0.227009 AN: 0.227009

Gnomad4 FIN AF: 0.396 AC: 0.395684 AN: 0.395684

Gnomad4 NFE AF: 0.392 AC: 0.392257 AN: 0.392257

Gnomad4 OTH AF: 0.262 AC: 0.261589 AN: 0.261589

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;.;.;.
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
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

Publications

LitVar

Other links and lift over

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