10-102597285-C-G

Position:

• chr10-102597285-C-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PP2 PP3

The NM_016169.4(SUFU):​c.902C>G​(p.Ser301Cys) variant causes a missense change involving the alteration of a 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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.57

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 6 ACMG points.

• PM1: In a modified_residue Phosphoserine (size 0) in uniprot entity SUFU_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), SUFU. . Gene score misZ 1.9341 (greater than the threshold 3.09). Trascript score misZ 3.1202 (greater than threshold 3.09). GenCC has associacion of gene with apraxia, ciliopathy, ocular motor apraxia, Cogan type, nevoid basal cell carcinoma syndrome, Joubert syndrome, Joubert syndrome 32, medulloblastoma.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.836

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SUFU	NM_016169.4	c.902C>G	p.Ser301Cys	missense_variant	7/12	ENST00000369902.8	NP_057253.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SUFU	ENST00000369902.8	c.902C>G	p.Ser301Cys	missense_variant	7/12	1	NM_016169.4	ENSP00000358918	P1
SUFU	ENST00000423559.2	c.902C>G	p.Ser301Cys	missense_variant	7/10	1		ENSP00000411597
SUFU	ENST00000369899.6	c.902C>G	p.Ser301Cys	missense_variant	7/11	1		ENSP00000358915
SUFU	ENST00000471000.1	n.684C>G		non_coding_transcript_exon_variant	5/6	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

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

Labcorp Genetics (formerly Invitae), Labcorp

Jun 18, 2018

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 (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with SUFU-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces serine with cysteine at codon 301 of the SUFU protein (p.Ser301Cys). The serine residue is highly conserved and there is a moderate physicochemical difference between serine and cysteine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.060
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Benign	0.38	T;.;.
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.88
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D;D;D
M_CAP	Uncertain	0.11	D
MetaRNN	Pathogenic	0.84	D;D;D
MetaSVM	Uncertain	0.021	D
MutationAssessor	Benign	1.7	L;L;L
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.79	T
PROVEAN	Benign	-1.9	N;N;N
REVEL	Uncertain	0.49
Sift	Uncertain	0.0040	D;D;D
Sift4G	Uncertain	0.022	D;D;D
Polyphen		1.0	D;D;D
Vest4		0.79
MutPred		0.53		Loss of phosphorylation at S301 (P = 0.0042);Loss of phosphorylation at S301 (P = 0.0042);Loss of phosphorylation at S301 (P = 0.0042);
MVP		0.51
MPC		1.5
ClinPred		0.97	D
GERP RS		6.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.27
gMVP		0.70

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

LitVar

Other links and lift over

dbSNP: rs1554852823; hg19: chr10-104357042;