chr11-407126-G-C
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Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong
The NM_001135054.2(SIGIRR):āc.664C>Gā(p.Arg222Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000159 in 1,562,134 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 (ā ).
Frequency
Genomes: š 0.00012 ( 0 hom., cov: 29)
Exomes š: 0.00016 ( 0 hom. )
Consequence
SIGIRR
NM_001135054.2 missense
NM_001135054.2 missense
Scores
6
8
4
Clinical Significance
Conservation
PhyloP100: 2.62
Genes affected
SIGIRR (HGNC:30575): (single Ig and TIR domain containing) Predicted to enable NAD+ nucleosidase activity. Involved in negative regulation of DNA-binding transcription factor activity. Located in membrane. [provided by Alliance of Genome Resources, Apr 2022]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.961
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SIGIRR | NM_001135054.2 | c.664C>G | p.Arg222Gly | missense_variant | 7/10 | ENST00000431843.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SIGIRR | ENST00000431843.7 | c.664C>G | p.Arg222Gly | missense_variant | 7/10 | 1 | NM_001135054.2 | P1 |
Frequencies
GnomAD3 genomes AF: 0.000120 AC: 18AN: 150058Hom.: 0 Cov.: 29
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GnomAD3 exomes AF: 0.0000598 AC: 11AN: 183928Hom.: 0 AF XY: 0.0000489 AC XY: 5AN XY: 102170
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GnomAD4 exome AF: 0.000163 AC: 230AN: 1412076Hom.: 0 Cov.: 33 AF XY: 0.000163 AC XY: 114AN XY: 700988
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GnomAD4 genome AF: 0.000120 AC: 18AN: 150058Hom.: 0 Cov.: 29 AF XY: 0.0000955 AC XY: 7AN XY: 73274
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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 | Oct 29, 2021 | The c.664C>G (p.R222G) alteration is located in exon 7 (coding exon 6) of the SIGIRR gene. This alteration results from a C to G substitution at nucleotide position 664, causing the arginine (R) at amino acid position 222 to be replaced by a glycine (G). 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
DEOGEN2
Benign
T;T;T;T;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D;D
MetaSVM
Benign
T
MutationAssessor
Pathogenic
M;M;M;.;.
MutationTaster
Benign
D;D;D;D;D
PrimateAI
Pathogenic
D
PROVEAN
Pathogenic
D;D;D;D;D
REVEL
Uncertain
Sift
Uncertain
D;D;D;D;D
Sift4G
Uncertain
D;D;D;D;D
Polyphen
D;D;D;D;.
Vest4
MutPred
Loss of MoRF binding (P = 0.0516);Loss of MoRF binding (P = 0.0516);Loss of MoRF binding (P = 0.0516);Loss of MoRF binding (P = 0.0516);.;
MVP
MPC
ClinPred
D
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