chr10-102594024-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_016169.4(SUFU):​c.715C>G​(p.Arg239Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Consequence

SUFU
NM_016169.4 missense

Scores

6
11
2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.48
Variant links:
Genes affected
SUFU (HGNC:16466): (SUFU negative regulator of hedgehog signaling) The Hedgehog signaling pathway plays an important role in early human development. The pathway is a signaling cascade that plays a role in pattern formation and cellular proliferation during development. This gene encodes a negative regulator of the hedgehog signaling pathway. Defects in this gene are a cause of medulloblastoma. Alternative splicing results in multiple transcript variants.[provided by RefSeq, May 2010]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.888

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
SUFUNM_016169.4 linkc.715C>G p.Arg239Gly missense_variant 6/12 ENST00000369902.8 NP_057253.2 Q9UMX1-1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
SUFUENST00000369902.8 linkc.715C>G p.Arg239Gly missense_variant 6/121 NM_016169.4 ENSP00000358918.4 Q9UMX1-1
SUFUENST00000423559.2 linkc.715C>G p.Arg239Gly missense_variant 6/101 ENSP00000411597.2 Q9UMX1-3
SUFUENST00000369899.6 linkc.715C>G p.Arg239Gly missense_variant 6/111 ENSP00000358915.2 Q9UMX1-2
SUFUENST00000471000.1 linkn.497C>G non_coding_transcript_exon_variant 4/65

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Gorlin syndrome;C0025149:Medulloblastoma Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpFeb 26, 2018This variant is not present in population databases (ExAC no frequency). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with SUFU-related disease. This sequence change replaces arginine with glycine at codon 239 of the SUFU protein (p.Arg239Gly). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and glycine. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.98
BayesDel_addAF
Pathogenic
0.37
D
BayesDel_noAF
Pathogenic
0.29
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.64
D;.;.
Eigen
Uncertain
0.50
Eigen_PC
Uncertain
0.49
FATHMM_MKL
Uncertain
0.82
D
LIST_S2
Uncertain
0.96
D;D;D
M_CAP
Uncertain
0.17
D
MetaRNN
Pathogenic
0.89
D;D;D
MetaSVM
Uncertain
0.36
D
MutationAssessor
Uncertain
2.4
M;M;M
PrimateAI
Pathogenic
0.82
D
PROVEAN
Uncertain
-4.4
D;D;D
REVEL
Pathogenic
0.69
Sift
Uncertain
0.027
D;D;D
Sift4G
Benign
0.11
T;T;T
Polyphen
0.98
D;D;D
Vest4
0.87
MutPred
0.44
Loss of stability (P = 0.0596);Loss of stability (P = 0.0596);Loss of stability (P = 0.0596);
MVP
0.85
MPC
1.8
ClinPred
0.99
D
GERP RS
5.0
Varity_R
0.85
gMVP
0.80

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.31
Details are displayed if max score is > 0.2
DS_AL_spliceai
0.31
Position offset: -31

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs369465986; hg19: chr10-104353781; API