5-353755-T-C

Variant names:

• chr5-353755-T-C
• rs201437247
• NM_001377236.1:c.88T>C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001377236.1(AHRR):​c.88T>C​(p.Ser30Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00022 in 1,612,130 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: 𝑓 0.00011 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00023 (0 hom.)
• Consequence: AHRR NM_001377236.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.700

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.19430014).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AHRR	NM_001377236.1	c.88T>C	p.Ser30Pro	missense_variant	Exon 3 of 11	ENST00000684583.1	NP_001364165.1
AHRR	NM_001377239.1	c.88T>C	p.Ser30Pro	missense_variant	Exon 3 of 11		NP_001364168.1
PDCD6-AHRR	NR_165159.2	n.381T>C		non_coding_transcript_exon_variant	Exon 5 of 14
PDCD6-AHRR	NR_165163.2	n.381T>C		non_coding_transcript_exon_variant	Exon 5 of 13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AHRR	ENST00000684583.1	c.88T>C	p.Ser30Pro	missense_variant	Exon 3 of 11		NM_001377236.1	ENSP00000507476.1
PDCD6-AHRR	ENST00000675395.1	n.*84T>C		non_coding_transcript_exon_variant	Exon 5 of 14			ENSP00000502570.1
PDCD6-AHRR	ENST00000675395.1	n.*84T>C		3_prime_UTR_variant	Exon 5 of 14			ENSP00000502570.1

Frequencies

GnomAD3 genomes AF: 0.000105 AC: 16 AN: 152048 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000725

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000189

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000142 AC: 35 AN: 247048 Hom.: 0 AF XY: 0.000134 AC XY: 18 AN XY: 134340

Gnomad AFR exome AF: 0.0000648

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000193

Gnomad NFE exome AF: 0.000214

Gnomad OTH exome AF: 0.000166

GnomAD4 exome AF: 0.000232 AC: 339 AN: 1459964 Hom.: 0 Cov.: 31 AF XY: 0.000238 AC XY: 173 AN XY: 726312

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000448

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000173

Gnomad4 NFE exome AF: 0.000284

Gnomad4 OTH exome AF: 0.000199

GnomAD4 genome AF: 0.000105 AC: 16 AN: 152166 Hom.: 0 Cov.: 33 AF XY: 0.000121 AC XY: 9 AN XY: 74390

Gnomad4 AFR AF: 0.0000723

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000189

Gnomad4 NFE AF: 0.000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000115 Hom.: 0

Bravo AF: 0.000102

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.00104 AC: 4

ExAC AF: 0.000149 AC: 18

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 04, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.100T>C (p.S34P) alteration is located in exon 3 (coding exon 3) of the AHRR gene. This alteration results from a T to C substitution at nucleotide position 100, causing the serine (S) at amino acid position 34 to be replaced by a proline (P). 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	0.57
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.24
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.60	D;.;.;.;.
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Benign	0.66	D
LIST_S2	Uncertain	0.94	D;D;D;D;D
M_CAP	Benign	0.028	D
MetaRNN	Benign	0.19	T;T;T;T;T
MetaSVM	Benign	-0.33	T
MutationAssessor	Pathogenic	3.4	M;M;.;.;.
PrimateAI	Uncertain	0.66	T
PROVEAN	Uncertain	-3.4	D;D;D;D;D
REVEL	Benign	0.18
Sift	Benign	0.044	D;D;T;D;D
Sift4G	Uncertain	0.0020	.;.;D;D;D
Polyphen		1.0	D;D;.;.;.
Vest4		0.52
MVP		0.84
MPC		1.8
ClinPred		0.59	D
GERP RS		2.4
Varity_R		0.61
gMVP		0.80

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: rs201437247; hg19: chr5-353870;