10-102504324-G-C

Variant names:

• chr10-102504324-G-C
• rs766897671
• NM_016169.4:c.172G>C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_016169.4(SUFU):​c.172G>C​(p.Val58Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,804 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SUFU NM_016169.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 5.81

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2006048).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SUFU	NM_016169.4	c.172G>C	p.Val58Leu	missense_variant	Exon 1 of 12	ENST00000369902.8	NP_057253.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SUFU	ENST00000369902.8	c.172G>C	p.Val58Leu	missense_variant	Exon 1 of 12	1	NM_016169.4	ENSP00000358918.4
SUFU	ENST00000423559.2	c.172G>C	p.Val58Leu	missense_variant	Exon 1 of 10	1		ENSP00000411597.2
SUFU	ENST00000369899.6	c.172G>C	p.Val58Leu	missense_variant	Exon 1 of 11	1		ENSP00000358915.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461804 Hom.: 0 Cov.: 53 AF XY: 0.00000138 AC XY: 1 AN XY: 727198

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Gorlin syndrome;C0025149:Medulloblastoma Uncertain:1

Aug 03, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 not expected to disrupt SUFU protein function. ClinVar contains an entry for this variant (Variation ID: 582250). This variant has not been reported in the literature in individuals affected with SUFU-related conditions. This variant is present in population databases (rs766897671, gnomAD 0.003%). This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 58 of the SUFU protein (p.Val58Leu). -

Hereditary cancer-predisposing syndrome Uncertain:1

Sep 24, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.V58L variant (also known as c.172G>C), located in coding exon 1 of the SUFU gene, results from a G to C substitution at nucleotide position 172. The valine at codon 58 is replaced by leucine, an amino acid with highly similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. 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	Benign	0.26
BayesDel_addAF	Benign	-0.096	T
BayesDel_noAF	Benign	-0.28
CADD	Uncertain	25
DANN	Benign	0.93
DEOGEN2	Benign	0.20	T;.;.
Eigen	Benign	-0.26
Eigen_PC	Benign	-0.029
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Uncertain	0.90	D;D;D
M_CAP	Uncertain	0.092	D
MetaRNN	Benign	0.20	T;T;T
MetaSVM	Benign	-0.70	T
MutationAssessor	Benign	0.80	N;N;N
PrimateAI	Pathogenic	0.89	D
PROVEAN	Benign	-0.72	N;N;N
REVEL	Benign	0.27
Sift	Benign	0.60	T;T;T
Sift4G	Benign	0.83	T;T;T
Polyphen		0.0020	B;B;B
Vest4		0.19
MutPred		0.49		Loss of sheet (P = 0.0025);Loss of sheet (P = 0.0025);Loss of sheet (P = 0.0025);
MVP		0.28
MPC		0.60
ClinPred		0.40	T
GERP RS		4.7
Varity_R		0.46
gMVP		0.60

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.15		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: rs766897671; hg19: chr10-104264081;