10-102615395-T-C

Position:

• chr10-102615395-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP2 PP3_Moderate

The NM_016169.4(SUFU):​c.1150T>C​(p.Cys384Arg) 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: 31)
• Consequence: SUFU NM_016169.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 7.67

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 5 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.923

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SUFU	NM_016169.4	c.1150T>C	p.Cys384Arg	missense_variant	9/12	ENST00000369902.8	NP_057253.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SUFU	ENST00000369902.8	c.1150T>C	p.Cys384Arg	missense_variant	9/12	1	NM_016169.4	ENSP00000358918.4
SUFU	ENST00000423559.2	c.1150T>C	p.Cys384Arg	missense_variant	9/10	1		ENSP00000411597.2
SUFU	ENST00000369899.6	c.1150T>C	p.Cys384Arg	missense_variant	9/11	1		ENSP00000358915.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

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

Labcorp Genetics (formerly Invitae), Labcorp

Jun 05, 2017

In summary, this variant has uncertain impact on SUFU function. The available evidence is currently insufficient to determine its role 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 do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with a SUFU-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces cysteine with arginine at codon 384 of the SUFU protein (p.Cys384Arg). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and arginine. -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 15, 2024

The p.C384R variant (also known as c.1150T>C), located in coding exon 9 of the SUFU gene, results from a T to C substitution at nucleotide position 1150. The cysteine at codon 384 is replaced by arginine, an amino acid with highly dissimilar properties. This amino acid position is conserved. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.27	T;.;.
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.95	D;D;D
M_CAP	Benign	0.056	D
MetaRNN	Pathogenic	0.92	D;D;D
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	1.4	L;L;L
PrimateAI	Pathogenic	0.94	D
PROVEAN	Benign	-1.6	N;N;N
REVEL	Uncertain	0.51
Sift	Uncertain	0.0050	D;D;D
Sift4G	Uncertain	0.0080	D;D;D
Polyphen		0.75	P;P;P
Vest4		0.93
MutPred		0.81		Gain of MoRF binding (P = 0.0064);Gain of MoRF binding (P = 0.0064);Gain of MoRF binding (P = 0.0064);
MVP		0.56
MPC		1.5
ClinPred		0.89	D
GERP RS		5.2
Varity_R		0.93
gMVP		0.95

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: rs375419295; hg19: chr10-104375152;