10-102504195-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 5P and 2B. PM2 PM5 PP2 BP4_Moderate

The NM_016169.4(SUFU):c.43C>G(p.Pro15Ala) 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 benign outcome for this variant. 13/21 in silico tools predict a benign 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. P15L) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: SUFU NM_016169.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 1.15

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr10-102504196-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 3569.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP2: Missense variant where missense usually causes diseases, SUFU
• BP4: Computational evidence support a benign effect (MetaRNN=0.11332199).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SUFU	NM_016169.4	c.43C>G	p.Pro15Ala	missense_variant	1/12	ENST00000369902.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SUFU	ENST00000369902.8	c.43C>G	p.Pro15Ala	missense_variant	1/12	1	NM_016169.4	P1
SUFU	ENST00000423559.2	c.43C>G	p.Pro15Ala	missense_variant	1/10	1
SUFU	ENST00000369899.6	c.43C>G	p.Pro15Ala	missense_variant	1/11	1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 46

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Gorlin syndrome;C0025149:Medulloblastoma Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

May 27, 2021

The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the ExAC database. This sequence change replaces proline with alanine at codon 15 of the SUFU protein (p.Pro15Ala). The proline residue is weakly conserved and there is a small physicochemical difference between proline and alanine. This variant has not been reported in the literature in individuals with SUFU-related conditions. 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 are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 22, 2022

The p.P15A variant (also known as c.43C>G), located in coding exon 1 of the SUFU gene, results from a C to G substitution at nucleotide position 43. The proline at codon 15 is replaced by alanine, 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	0.047
BayesDel_addAF	Benign	-0.034	T
BayesDel_noAF	Benign	-0.29
Cadd	Benign	19
Dann	Uncertain	0.98
DEOGEN2	Benign	0.13	T;.;.
Eigen	Benign	-0.59
Eigen_PC	Benign	-0.39
FATHMM_MKL	Benign	0.60	D
LIST_S2	Uncertain	0.88	D;D;D
M_CAP	Uncertain	0.17	D
MetaRNN	Benign	0.11	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.34	N;N;N
MutationTaster	Benign	0.94	N;N;N
PrimateAI	Pathogenic	0.80	T
PROVEAN	Benign	0.46	N;N;N
REVEL	Benign	0.088
Sift	Benign	0.047	D;D;D
Sift4G	Benign	0.94	T;T;T
Polyphen		0.0	B;B;B
Vest4		0.27
MutPred		0.16		Loss of glycosylation at P15 (P = 0.0057);Loss of glycosylation at P15 (P = 0.0057);Loss of glycosylation at P15 (P = 0.0057);
MVP		0.32
MPC		1.1
ClinPred		0.28	T
GERP RS		3.5
Varity_R		0.071
gMVP		0.51

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: chr10-104263952;