20-35006462-G-C
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Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2
The NM_015638.3(TRPC4AP):āc.1800C>Gā(p.Phe600Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000316 in 1,614,082 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (ā ).
Frequency
Genomes: š 0.000033 ( 0 hom., cov: 33)
Exomes š: 0.000031 ( 0 hom. )
Consequence
TRPC4AP
NM_015638.3 missense
NM_015638.3 missense
Scores
3
7
7
Clinical Significance
Conservation
PhyloP100: 2.39
Genes affected
TRPC4AP (HGNC:16181): (transient receptor potential cation channel subfamily C member 4 associated protein) Enables phosphatase binding activity and ubiquitin ligase-substrate adaptor activity. Involved in protein ubiquitination and ubiquitin-dependent protein catabolic process via the C-end degron rule pathway. Part of Cul4A-RING E3 ubiquitin ligase complex. Is active in Cul4-RING E3 ubiquitin ligase complex. [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 AC in GnomAd4 at 5 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TRPC4AP | NM_015638.3 | c.1800C>G | p.Phe600Leu | missense_variant | 15/19 | ENST00000252015.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TRPC4AP | ENST00000252015.3 | c.1800C>G | p.Phe600Leu | missense_variant | 15/19 | 1 | NM_015638.3 | P4 | |
TRPC4AP | ENST00000451813.6 | c.1776C>G | p.Phe592Leu | missense_variant | 15/19 | 2 | A1 |
Frequencies
GnomAD3 genomes AF: 0.0000329 AC: 5AN: 152204Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000477 AC: 12AN: 251482Hom.: 0 AF XY: 0.0000368 AC XY: 5AN XY: 135914
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GnomAD4 exome AF: 0.0000315 AC: 46AN: 1461878Hom.: 0 Cov.: 33 AF XY: 0.0000220 AC XY: 16AN XY: 727238
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GnomAD4 genome AF: 0.0000329 AC: 5AN: 152204Hom.: 0 Cov.: 33 AF XY: 0.0000404 AC XY: 3AN XY: 74338
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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 | Feb 15, 2023 | The c.1800C>G (p.F600L) alteration is located in exon 15 (coding exon 15) of the TRPC4AP gene. This alteration results from a C to G substitution at nucleotide position 1800, causing the phenylalanine (F) at amino acid position 600 to be replaced by a leucine (L). 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
Benign
T
BayesDel_noAF
Uncertain
CADD
Uncertain
DANN
Uncertain
Eigen
Uncertain
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D
M_CAP
Benign
D
MetaRNN
Uncertain
T;T
MetaSVM
Benign
T
MutationTaster
Benign
D;D;D;D
PrimateAI
Pathogenic
D
PROVEAN
Benign
N;N
REVEL
Uncertain
Sift
Benign
T;T
Sift4G
Pathogenic
D;D
Polyphen
1.0
.;D
Vest4
MutPred
0.66
.;Loss of methylation at K602 (P = 0.1016);
MVP
MPC
1.1
ClinPred
T
GERP RS
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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