10-102627177-T-C

Position:

chr10-102627177-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_016169.4(SUFU):c.1299T>C(p.Ile433Ile) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.114 in 1,613,514 control chromosomes in the GnomAD database, including 15,918 homozygotes. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.15 ( 2263 hom., cov: 32)

Exomes 𝑓: 0.11 ( 13655 hom. )

Consequence

SUFU
NM_016169.4 splice_region, synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 0.661

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 Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.54).

BP6

Variant 10-102627177-T-C is Benign according to our data. Variant chr10-102627177-T-C is described in ClinVar as [Benign]. Clinvar id is 260687.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-102627177-T-C is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=0.661 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.401 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SUFU	NM_016169.4 linkuse as main transcript	c.1299T>C	p.Ile433Ile	splice_region_variant, synonymous_variant	11/12	ENST00000369902.8	NP_057253.2	Q9UMX1-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SUFU	ENST00000369902.8 linkuse as main transcript	c.1299T>C	p.Ile433Ile	splice_region_variant, synonymous_variant	11/12	1	NM_016169.4	ENSP00000358918.4		Q9UMX1-1

Frequencies

GnomAD3 genomes

AF:

0.151

AC:

23040

AN:

152144

Hom.:

2255

Cov.:

show subpopulations

Gnomad AFR

AF:

0.219

Gnomad AMI

AF:

0.122

Gnomad AMR

AF:

0.193

Gnomad ASJ

AF:

0.0643

Gnomad EAS

AF:

0.416

Gnomad SAS

AF:

0.222

Gnomad FIN

AF:

0.0725

Gnomad MID

AF:

0.0823

Gnomad NFE

AF:

0.0931

Gnomad OTH

AF:

0.163

GnomAD3 exomes

AF:

0.160

AC:

40291

AN:

251478

Hom.:

4675

AF XY:

0.155

AC XY:

21016

AN XY:

135908

show subpopulations

Gnomad AFR exome

AF:

0.224

Gnomad AMR exome

AF:

0.267

Gnomad ASJ exome

AF:

0.0715

Gnomad EAS exome

AF:

0.413

Gnomad SAS exome

AF:

0.225

Gnomad FIN exome

AF:

0.0745

Gnomad NFE exome

AF:

0.0863

Gnomad OTH exome

AF:

0.124

GnomAD4 exome

AF:

0.111

AC:

161590

AN:

1461254

Hom.:

13655

Cov.:

AF XY:

0.113

AC XY:

82193

AN XY:

726982

show subpopulations

Gnomad4 AFR exome

AF:

0.221

Gnomad4 AMR exome

AF:

0.261

Gnomad4 ASJ exome

AF:

0.0679

Gnomad4 EAS exome

AF:

0.447

Gnomad4 SAS exome

AF:

0.226

Gnomad4 FIN exome

AF:

0.0753

Gnomad4 NFE exome

AF:

0.0823

Gnomad4 OTH exome

AF:

0.123

GnomAD4 genome

AF:

0.152

AC:

23084

AN:

152260

Hom.:

2263

Cov.:

AF XY:

0.154

AC XY:

11484

AN XY:

74450

show subpopulations

Gnomad4 AFR

AF:

0.219

Gnomad4 AMR

AF:

0.194

Gnomad4 ASJ

AF:

0.0643

Gnomad4 EAS

AF:

0.416

Gnomad4 SAS

AF:

0.222

Gnomad4 FIN

AF:

0.0725

Gnomad4 NFE

AF:

0.0931

Gnomad4 OTH

AF:

0.166

Alfa

AF:

0.108

Hom.:

2730

Bravo

AF:

0.166

Asia WGS

AF:

0.314

AC:

1086

AN:

3478

EpiCase

AF:

0.0887

EpiControl

AF:

0.0870

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 31, 2016	Variant summary: The SUFU c.1299T>C (p.Ile433Ile) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. One in silico tool predicts a polymorphism outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing. ESE finder predicts that this variant may affect ESE site of SC35. However, these predictions have yet to be confirmed by functional studies. This variant was found in 19257/121358 control chromosomes (2233 homozygotes) at a frequency of 0.1586793, which is significantly higher than the estimated maximal expected allele frequency of a pathogenic SUFU variant (0.000001), suggesting this variant is likely a benign polymorphism. Taken together, this variant is classified as benign. -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

- -

Gorlin syndrome;C0025149:Medulloblastoma

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Familial meningioma

Benign:1

Benign, criteria provided, single submitter

clinical testing

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Jul 07, 2023

- -

Medulloblastoma

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Hereditary cancer-predisposing syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 09, 2016

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.54

CADD

Benign

DANN

Benign

0.63

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