chr12-108518778-T-C
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3
The NM_007076.3(FICD):c.680T>C(p.Ile227Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000434 in 1,614,018 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 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000041 ( 0 hom. )
Consequence
FICD
NM_007076.3 missense
NM_007076.3 missense
Scores
7
5
7
Clinical Significance
Conservation
PhyloP100: 7.95
Genes affected
FICD (HGNC:18416): (FIC domain protein adenylyltransferase) Enables several functions, including ATP binding activity; Hsp70 protein binding activity; and chaperone binding activity. Involved in protein adenylylation; regulation of IRE1-mediated unfolded protein response; and response to endoplasmic reticulum stress. Is integral component of endoplasmic reticulum membrane. [provided by Alliance of Genome Resources, Apr 2022]
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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, 0.815
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FICD | NM_007076.3 | c.680T>C | p.Ile227Thr | missense_variant | 3/3 | ENST00000552695.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FICD | ENST00000552695.6 | c.680T>C | p.Ile227Thr | missense_variant | 3/3 | 1 | NM_007076.3 | P1 | |
FICD | ENST00000361549.2 | c.*417T>C | 3_prime_UTR_variant | 3/3 | 1 | ||||
FICD | ENST00000549641.1 | c.153+1505T>C | intron_variant | 3 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152130Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00000797 AC: 2AN: 250964Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135634
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GnomAD4 exome AF: 0.00000410 AC: 6AN: 1461888Hom.: 0 Cov.: 33 AF XY: 0.00000413 AC XY: 3AN XY: 727242
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GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152130Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74310
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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 | Jun 01, 2023 | The c.680T>C (p.I227T) alteration is located in exon 3 (coding exon 2) of the FICD gene. This alteration results from a T to C substitution at nucleotide position 680, causing the isoleucine (I) at amino acid position 227 to be replaced by a threonine (T). 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
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Uncertain
DEOGEN2
Benign
T
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
D
M_CAP
Benign
T
MetaRNN
Pathogenic
D
MetaSVM
Benign
T
MutationAssessor
Benign
N
MutationTaster
Benign
D;D
PrimateAI
Pathogenic
D
PROVEAN
Uncertain
D
REVEL
Uncertain
Sift
Benign
T
Sift4G
Benign
T
Polyphen
D
Vest4
MutPred
Gain of catalytic residue at I227 (P = 0.0123);
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