chr5-376676-T-C

Position:

• chr5-376676-T-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001377236.1(AHRR):​c.311T>C​(p.Leu104Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L104V) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: AHRR NM_001377236.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -2.64

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06125155).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AHRR	NM_001377236.1	c.311T>C	p.Leu104Pro	missense_variant	4/11	ENST00000684583.1
PDCD6-AHRR	NR_165159.2	n.604T>C		non_coding_transcript_exon_variant	6/14
AHRR	NM_001377239.1	c.311T>C	p.Leu104Pro	missense_variant	4/11
PDCD6-AHRR	NR_165163.2	n.604T>C		non_coding_transcript_exon_variant	6/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AHRR	ENST00000684583.1	c.311T>C	p.Leu104Pro	missense_variant	4/11		NM_001377236.1	P1
AHRR	ENST00000316418.10	c.311T>C	p.Leu104Pro	missense_variant	4/11	1		P1
AHRR	ENST00000510400.5	c.311T>C	p.Leu104Pro	missense_variant	4/6	4
AHRR	ENST00000514523.1	c.-140T>C		5_prime_UTR_variant	4/6	4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 33

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

Mar 02, 2023

The c.323T>C (p.L108P) alteration is located in exon 4 (coding exon 4) of the AHRR gene. This alteration results from a T to C substitution at nucleotide position 323, causing the leucine (L) at amino acid position 108 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	Benign	0.046
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	0.018
DANN	Benign	0.39
DEOGEN2	Benign	0.047	T;.;.
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.010	N
LIST_S2	Benign	0.22	T;T;T
M_CAP	Benign	0.0015	T
MetaRNN	Benign	0.061	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.34	N;N;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	0.49	N;N;N
REVEL	Benign	0.026
Sift	Benign	0.24	T;T;T
Sift4G	Benign	0.25	.;.;T
Polyphen		0.0	B;B;.
Vest4		0.065
MutPred		0.51		Gain of disorder (P = 0.011);Gain of disorder (P = 0.011);.;
MVP		0.27
MPC		0.94
ClinPred		0.12	T
GERP RS		-5.6
Varity_R		0.14
gMVP		0.36

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr5-376791;