chr17-81956658-G-A
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Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2
The NM_178493.6(NOTUM):c.980C>T(p.Thr327Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000276 in 1,610,240 control chromosomes in the GnomAD database, including 2 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.00022 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00028 ( 2 hom. )
Consequence
NOTUM
NM_178493.6 missense
NM_178493.6 missense
Scores
3
13
3
Clinical Significance
Conservation
PhyloP100: 7.28
Genes affected
NOTUM (HGNC:27106): (notum, palmitoleoyl-protein carboxylesterase) Enables palmitoleyl hydrolase activity. Involved in negative regulation of Wnt signaling pathway and protein depalmitoleylation. Acts upstream of or within bone development and regulation of bone mineralization. Predicted to be located in endoplasmic reticulum lumen and extracellular region. [provided by Alliance of Genome Resources, Apr 2022]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -4 ACMG points.
BS2
High Homozygotes in GnomAdExome4 at 2 gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NOTUM | NM_178493.6 | c.980C>T | p.Thr327Ile | missense_variant | 8/11 | ENST00000409678.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NOTUM | ENST00000409678.8 | c.980C>T | p.Thr327Ile | missense_variant | 8/11 | 1 | NM_178493.6 | P1 | |
NOTUM | ENST00000477214.5 | c.554C>T | p.Thr185Ile | missense_variant | 7/8 | 5 |
Frequencies
GnomAD3 genomes AF: 0.000223 AC: 34AN: 152206Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.000193 AC: 48AN: 248576Hom.: 0 AF XY: 0.000215 AC XY: 29AN XY: 135068
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GnomAD4 exome AF: 0.000282 AC: 411AN: 1458034Hom.: 2 Cov.: 30 AF XY: 0.000284 AC XY: 206AN XY: 725522
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GnomAD4 genome AF: 0.000223 AC: 34AN: 152206Hom.: 0 Cov.: 33 AF XY: 0.000215 AC XY: 16AN XY: 74368
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 21, 2022 | The c.980C>T (p.T327I) alteration is located in exon 8 (coding exon 8) of the NOTUM gene. This alteration results from a C to T substitution at nucleotide position 980, causing the threonine (T) at amino acid position 327 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Uncertain
T;T
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D
M_CAP
Uncertain
D
MetaRNN
Uncertain
T;T
MetaSVM
Uncertain
D
MutationAssessor
Pathogenic
M;.
MutationTaster
Benign
D
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;.
REVEL
Uncertain
Sift
Uncertain
D;.
Sift4G
Uncertain
D;.
Polyphen
D;.
Vest4
MVP
MPC
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at