chr14-36662975-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2PM5PP3_Strong

The NM_001372076.1(PAX9):​c.83G>T​(p.Arg28Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,264 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R28P) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

PAX9
NM_001372076.1 missense

Scores

15
3
1

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 10.0
Variant links:
Genes affected
PAX9 (HGNC:8623): (paired box 9) This gene is a member of the paired box (PAX) family of transcription factors. Members of this gene family typically contain a paired box domain, an octapeptide, and a paired-type homeodomain. These genes play critical roles during fetal development and cancer growth. Mice lacking this gene exhibit impaired development of organs, musculature and the skeleton, including absent and abnormally developed teeth, and neonatal lethality. Mutations in the human gene are associated with selective tooth agenesis-3. [provided by RefSeq, Sep 2015]

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr14-36662975-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 13773.Status of the report is no_assertion_criteria_provided, 0 stars.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.959

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
PAX9NM_001372076.1 linkuse as main transcriptc.83G>T p.Arg28Leu missense_variant 2/4 ENST00000361487.7
PAX9NM_006194.4 linkuse as main transcriptc.83G>T p.Arg28Leu missense_variant 3/5

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
PAX9ENST00000361487.7 linkuse as main transcriptc.83G>T p.Arg28Leu missense_variant 2/41 NM_001372076.1 P1
PAX9ENST00000402703.6 linkuse as main transcriptc.83G>T p.Arg28Leu missense_variant 3/55 P1
PAX9ENST00000555639.2 linkuse as main transcriptc.83G>T p.Arg28Leu missense_variant 3/35
PAX9ENST00000554201.1 linkuse as main transcriptn.402G>T non_coding_transcript_exon_variant 1/32

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461264
Hom.:
0
Cov.:
37
AF XY:
0.00000138
AC XY:
1
AN XY:
726944
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
8.99e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33
Bravo
AF:
0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.99
BayesDel_addAF
Pathogenic
0.54
D
BayesDel_noAF
Pathogenic
0.54
CADD
Pathogenic
35
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.91
D;D
Eigen
Pathogenic
0.86
Eigen_PC
Pathogenic
0.83
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.96
D;.
M_CAP
Pathogenic
0.73
D
MetaRNN
Pathogenic
0.96
D;D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Uncertain
2.2
M;M
MutationTaster
Benign
1.0
D;D;D
PrimateAI
Pathogenic
0.89
D
PROVEAN
Pathogenic
-6.8
D;D
REVEL
Pathogenic
0.93
Sift
Pathogenic
0.0
D;D
Sift4G
Pathogenic
0.0010
D;D
Polyphen
1.0
D;D
Vest4
0.95
MutPred
0.72
Loss of MoRF binding (P = 0.0661);Loss of MoRF binding (P = 0.0661);
MVP
0.99
MPC
3.4
ClinPred
1.0
D
GERP RS
5.1
Varity_R
0.89
gMVP
0.96

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs28933971; hg19: chr14-37132180; API