rs28942088

Positions:

• chr10-102504196-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM2 PP2 PP5 BP4

The NM_016169.4(SUFU):​c.44C>T​(p.Pro15Leu) 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. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P15A) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: SUFU NM_016169.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter P:1
• Conservation: PhyloP100: 1.87

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
• 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.
• PP5: Variant 10-102504196-C-T is Pathogenic according to our data. 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.15010923). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SUFU	NM_016169.4	c.44C>T	p.Pro15Leu	missense_variant	1/12	ENST00000369902.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SUFU	ENST00000369902.8	c.44C>T	p.Pro15Leu	missense_variant	1/12	1	NM_016169.4	P1
SUFU	ENST00000423559.2	c.44C>T	p.Pro15Leu	missense_variant	1/10	1
SUFU	ENST00000369899.6	c.44C>T	p.Pro15Leu	missense_variant	1/11	1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 46

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Medulloblastoma Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jul 01, 2002

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.094
BayesDel_addAF	Uncertain	0.014	T
BayesDel_noAF	Benign	-0.22
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.14	T;.;.
Eigen	Benign	-0.26
Eigen_PC	Benign	-0.082
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Uncertain	0.91	D;D;D
M_CAP	Uncertain	0.21	D
MetaRNN	Benign	0.15	T;T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	0.34	N;N;N
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	0.030	N;N;N
REVEL	Benign	0.11
Sift	Benign	0.033	D;D;D
Sift4G	Benign	0.38	T;T;T
Polyphen		0.0010	B;B;B
Vest4		0.28
MutPred		0.071		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		0.33
MPC		1.3
ClinPred		0.91	D
GERP RS		4.4
Varity_R		0.18
gMVP		0.52

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: rs28942088; hg19: chr10-104263953;