10-102504165-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2PP2BP4

The NM_016169.4(SUFU):c.13C>T(p.Arg5Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000324 in 1,544,840 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. R5R) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000022 ( 0 hom. )

Consequence

SUFU
NM_016169.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 1.76

Variant links:

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]

SUFU links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant where missense usually causes diseases, SUFU

BP4

Computational evidence support a benign effect (MetaRNN=0.41318035).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SUFU	NM_016169.4 linkuse as main transcript	c.13C>T	p.Arg5Trp	missense_variant	1/12	ENST00000369902.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SUFU	ENST00000369902.8 linkuse as main transcript	c.13C>T	p.Arg5Trp	missense_variant	1/12	1	NM_016169.4	P1	Q9UMX1-1
SUFU	ENST00000423559.2 linkuse as main transcript	c.13C>T	p.Arg5Trp	missense_variant	1/10	1			Q9UMX1-3
SUFU	ENST00000369899.6 linkuse as main transcript	c.13C>T	p.Arg5Trp	missense_variant	1/11	1			Q9UMX1-2

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152162

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000684

AC:

AN:

146198

Hom.:

AF XY:

0.0000126

AC XY:

AN XY:

79538

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000440

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000215

AC:

AN:

1392678

Hom.:

Cov.:

AF XY:

0.00000146

AC XY:

AN XY:

687018

show subpopulations

Gnomad4 AFR exome

AF:

0.0000315

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000126

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000173

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152162

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74316

show subpopulations

Gnomad4 AFR

AF:

0.0000483

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000151

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Gorlin syndrome;C0025149:Medulloblastoma

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Nov 15, 2023

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 5 of the SUFU protein (p.Arg5Trp). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with SUFU-related conditions. ClinVar contains an entry for this variant (Variation ID: 956096). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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. -

Familial meningioma

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

May 12, 2023

- -

Hereditary cancer-predisposing syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 11, 2024

The p.R5W variant (also known as c.13C>T), located in coding exon 1 of the SUFU gene, results from a C to T substitution at nucleotide position 13. The arginine at codon 5 is replaced by tryptophan, an amino acid with dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.60

BayesDel_addAF

Pathogenic

0.20

BayesDel_noAF

Uncertain

0.050

Cadd

Pathogenic

Dann

Uncertain

1.0

DEOGEN2

Benign

0.17

T;.;.

Eigen

Uncertain

0.41

Eigen_PC

Uncertain

0.38

FATHMM_MKL

Uncertain

0.83

LIST_S2

Uncertain

0.95

D;D;D

M_CAP

Pathogenic

0.91

MetaRNN

Benign

0.41

T;T;T

MetaSVM

Benign

-0.28

MutationAssessor

Benign

0.90

L;L;L

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Pathogenic

0.93

PROVEAN

Benign

-0.090

N;N;N

REVEL

Benign

0.27

Sift

Pathogenic

0.0

D;D;D

Sift4G

Uncertain

0.017

D;D;D

Polyphen

1.0

D;D;D

Vest4

0.29

MutPred

0.32

Loss of methylation at S5 (P = 0.015);Loss of methylation at S5 (P = 0.015);Loss of methylation at S5 (P = 0.015);

MVP

0.54

MPC

1.3

ClinPred

0.82

GERP RS

4.3

Varity_R

0.90

gMVP

0.73

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over