rs771255988

Variant names:

• chr10-102597275-C-G
• NM_016169.4:c.892C>G

Your query was ambiguous. Multiple possible variants found:

• chr10-102597275-C-G
• chr10-102597275-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_016169.4(SUFU):​c.892C>G​(p.Arg298Gly) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SUFU NM_016169.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 4.59

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SUFU	NM_016169.4	c.892C>G	p.Arg298Gly	missense_variant	Exon 7 of 12	ENST00000369902.8	NP_057253.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SUFU	ENST00000369902.8	c.892C>G	p.Arg298Gly	missense_variant	Exon 7 of 12	1	NM_016169.4	ENSP00000358918.4
SUFU	ENST00000423559.2	c.892C>G	p.Arg298Gly	missense_variant	Exon 7 of 10	1		ENSP00000411597.2
SUFU	ENST00000369899.6	c.892C>G	p.Arg298Gly	missense_variant	Exon 7 of 11	1		ENSP00000358915.2
SUFU	ENST00000471000.1	n.674C>G		non_coding_transcript_exon_variant	Exon 5 of 6	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Gorlin syndrome;C0025149:Medulloblastoma Uncertain:1

Oct 12, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 298 of the SUFU protein (p.Arg298Gly). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with SUFU-related conditions. 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 not expected to disrupt SUFU protein function. 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. -

not provided Uncertain:1

Feb 06, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The SUFU c.892C>G (p.Arg298Gly) variant has not been reported in individuals with SUFU-related conditions in the published literature. It also has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant. -

Hereditary cancer-predisposing syndrome Uncertain:1

Jan 13, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R298G variant (also known as c.892C>G), located in coding exon 7 of the SUFU gene, results from a C to G substitution at nucleotide position 892. The arginine at codon 298 is replaced by glycine, an amino acid with dissimilar properties. This amino acid position is conserved. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.50
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.11
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.16	T;.;.
Eigen	Uncertain	0.27
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.98	D;D;D
M_CAP	Uncertain	0.088	D
MetaRNN	Uncertain	0.71	D;D;D
MetaSVM	Benign	-0.45	T
MutationAssessor	Benign	1.7	L;L;L
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-0.72	N;N;N
REVEL	Uncertain	0.41
Sift	Benign	0.094	T;T;T
Sift4G	Benign	0.35	T;T;T
Polyphen		0.99	D;D;P
Vest4		0.85
MutPred		0.66		Gain of sheet (P = 0.039);Gain of sheet (P = 0.039);Gain of sheet (P = 0.039);
MVP		0.64
MPC		1.4
ClinPred		0.91	D
GERP RS		5.1
Varity_R		0.18
gMVP		0.65

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr10-104357032;