chr1-11194653-C-T
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3
The NM_021146.4(ANGPTL7):c.865C>T(p.Arg289Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000434 in 1,614,034 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000046 ( 0 hom. )
Consequence
ANGPTL7
NM_021146.4 missense
NM_021146.4 missense
Scores
3
8
8
Clinical Significance
Conservation
PhyloP100: 3.77
Genes affected
ANGPTL7 (HGNC:24078): (angiopoietin like 7) Enables identical protein binding activity. Involved in negative regulation of vasculature development involved in avascular cornea development in camera-type eye and regulation of extracellular matrix organization. Located in extracellular region. [provided by Alliance of Genome Resources, Apr 2022]
MTOR (HGNC:3942): (mechanistic target of rapamycin kinase) The protein encoded by this gene belongs to a family of phosphatidylinositol kinase-related kinases. These kinases mediate cellular responses to stresses such as DNA damage and nutrient deprivation. This kinase is a component of two distinct complexes, mTORC1, which controls protein synthesis, cell growth and proliferation, and mTORC2, which is a regulator of the actin cytoskeleton, and promotes cell survival and cell cycle progression. This protein acts as the target for the cell-cycle arrest and immunosuppressive effects of the FKBP12-rapamycin complex. Inhibitors of mTOR are used in organ transplants as immunosuppressants, and are being evaluated for their therapeutic potential in SARS-CoV-2 infections. Mutations in this gene are associated with Smith-Kingsmore syndrome and somatic focal cortical dysplasia type II. The ANGPTL7 gene is located in an intron of this gene. [provided by RefSeq, Aug 2020]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 3 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.816
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ANGPTL7 | NM_021146.4 | c.865C>T | p.Arg289Cys | missense_variant | 4/5 | ENST00000376819.4 | |
MTOR | NM_004958.4 | c.4253+4605G>A | intron_variant | ENST00000361445.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ANGPTL7 | ENST00000376819.4 | c.865C>T | p.Arg289Cys | missense_variant | 4/5 | 1 | NM_021146.4 | P1 | |
MTOR | ENST00000361445.9 | c.4253+4605G>A | intron_variant | 1 | NM_004958.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 152160Hom.: 0 Cov.: 32
GnomAD3 genomes
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GnomAD3 exomes AF: 0.0000199 AC: 5AN: 251138Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135730
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GnomAD4 exome AF: 0.0000458 AC: 67AN: 1461874Hom.: 0 Cov.: 31 AF XY: 0.0000413 AC XY: 30AN XY: 727238
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GnomAD4 genome ? AF: 0.0000197 AC: 3AN: 152160Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74324
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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 | Sep 14, 2023 | The c.865C>T (p.R289C) alteration is located in exon 4 (coding exon 4) of the ANGPTL7 gene. This alteration results from a C to T substitution at nucleotide position 865, causing the arginine (R) at amino acid position 289 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Uncertain
DEOGEN2
Benign
T
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Benign
N
LIST_S2
Uncertain
D
M_CAP
Benign
D
MetaRNN
Pathogenic
D
MetaSVM
Uncertain
T
MutationAssessor
Benign
L
MutationTaster
Benign
D;D
PrimateAI
Uncertain
T
PROVEAN
Benign
N
REVEL
Uncertain
Sift
Benign
T
Sift4G
Benign
T
Polyphen
D
Vest4
MutPred
Gain of methylation at K290 (P = 0.0295);
MVP
MPC
ClinPred
D
GERP RS
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