rs1060501106

chr10-102509262-C-G

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP2 PP3_Strong

The NM_016169.4(SUFU):c.276C>G(p.Ser92Arg) variant causes a missense change. 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S92T) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SUFU NM_016169.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.73

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, SUFU
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.967

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SUFU	NM_016169.4	c.276C>G	p.Ser92Arg	missense_variant	2/12	ENST00000369902.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SUFU	ENST00000369902.8	c.276C>G	p.Ser92Arg	missense_variant	2/12	1	NM_016169.4	P1
SUFU	ENST00000423559.2	c.276C>G	p.Ser92Arg	missense_variant	2/10	1
SUFU	ENST00000369899.6	c.276C>G	p.Ser92Arg	missense_variant	2/11	1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Gorlin syndrome;C0025149:Medulloblastoma Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Nov 15, 2022

This variant is not present in population databases (gnomAD 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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt SUFU protein function. ClinVar contains an entry for this variant (Variation ID: 406383). This variant has not been reported in the literature in individuals affected with SUFU-related conditions. This sequence change replaces serine, which is neutral and polar, with arginine, which is basic and polar, at codon 92 of the SUFU protein (p.Ser92Arg). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.38
Cadd	Pathogenic	28
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.88	D;.;.
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.95	D;D;D
M_CAP	Pathogenic	0.34	D
MetaRNN	Pathogenic	0.97	D;D;D
MetaSVM	Pathogenic	0.80	D
MutationAssessor	Pathogenic	3.5	M;M;M
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.76	T
PROVEAN	Uncertain	-4.1	D;D;D
REVEL	Pathogenic	0.91
Sift	Uncertain	0.0010	D;D;D
Sift4G	Uncertain	0.0020	D;D;D
Polyphen		1.0	D;D;D
Vest4		0.97
MutPred		0.83		Loss of sheet (P = 0.0126);Loss of sheet (P = 0.0126);Loss of sheet (P = 0.0126);
MVP		0.92
MPC		1.7
ClinPred		1.0	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.97
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs1060501106; hg19: chr10-104269019;