10-102593638-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6BP7BS1BS2

The NM_016169.4(SUFU):c.600C>T(p.Ile200=) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00177 in 1,614,112 control chromosomes in the GnomAD database, including 3 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 Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. I200I) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0012 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0018 ( 1 hom. )

Consequence

SUFU
NM_016169.4 splice_region, synonymous

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:13

Conservation

PhyloP100: 0.130

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 -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.49).

BP6

Variant 10-102593638-C-T is Benign according to our data. Variant chr10-102593638-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 413912.We mark this variant Likely_benign, oryginal submissions are: {Benign=3, Likely_benign=7, Uncertain_significance=1}. Variant chr10-102593638-C-T is described in Lovd as [Likely_benign].

BP7

Synonymous conserved (PhyloP=0.13 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0012 (182/152260) while in subpopulation NFE AF= 0.00188 (128/68028). AF 95% confidence interval is 0.00162. There are 2 homozygotes in gnomad4. There are 85 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd at 184 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SUFU	NM_016169.4 linkuse as main transcript	c.600C>T	p.Ile200=	splice_region_variant, synonymous_variant	5/12	ENST00000369902.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SUFU	ENST00000369902.8 linkuse as main transcript	c.600C>T	p.Ile200=	splice_region_variant, synonymous_variant	5/12	1	NM_016169.4	P1	Q9UMX1-1
SUFU	ENST00000423559.2 linkuse as main transcript	c.600C>T	p.Ile200=	splice_region_variant, synonymous_variant	5/10	1			Q9UMX1-3
SUFU	ENST00000369899.6 linkuse as main transcript	c.600C>T	p.Ile200=	splice_region_variant, synonymous_variant	5/11	1			Q9UMX1-2
SUFU	ENST00000471000.1 linkuse as main transcript	n.382C>T		splice_region_variant, non_coding_transcript_exon_variant	3/6	5

Frequencies

GnomAD3 genomes

AF:

0.00121

AC:

184

AN:

152142

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000411

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00105

Gnomad ASJ

AF:

0.000865

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000565

Gnomad MID

AF:

0.0316

Gnomad NFE

AF:

0.00188

Gnomad OTH

AF:

0.00144

GnomAD3 exomes

AF:

0.00131

AC:

329

AN:

251436

Hom.:

AF XY:

0.00143

AC XY:

195

AN XY:

135904

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.00110

Gnomad ASJ exome

AF:

0.00278

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.000131

Gnomad FIN exome

AF:

0.000416

Gnomad NFE exome

AF:

0.00209

Gnomad OTH exome

AF:

0.00130

GnomAD4 exome

AF:

0.00183

AC:

2671

AN:

1461852

Hom.:

Cov.:

AF XY:

0.00179

AC XY:

1302

AN XY:

727232

show subpopulations

Gnomad4 AFR exome

AF:

0.000388

Gnomad4 AMR exome

AF:

0.00114

Gnomad4 ASJ exome

AF:

0.00268

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.000128

Gnomad4 FIN exome

AF:

0.000225

Gnomad4 NFE exome

AF:

0.00217

Gnomad4 OTH exome

AF:

0.00147

GnomAD4 genome

AF:

0.00120

AC:

182

AN:

152260

Hom.:

Cov.:

AF XY:

0.00114

AC XY:

AN XY:

74466

show subpopulations

Gnomad4 AFR

AF:

0.000409

Gnomad4 AMR

AF:

0.00105

Gnomad4 ASJ

AF:

0.000865

Gnomad4 EAS

AF:

0.000194

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000565

Gnomad4 NFE

AF:

0.00188

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.00151

Hom.:

Bravo

AF:

0.00125

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00196

EpiControl

AF:

0.00290

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:13

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:6

Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 02, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	May 27, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2023	SUFU: BP4, BP7 -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 03, 2018	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not specified

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 09, 2017	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jun 22, 2021	- -

Hereditary cancer-predisposing syndrome

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Mar 07, 2019	This alteration is classified as likely 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. -
Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	May 06, 2021	- -

Gorlin syndrome;C0025149:Medulloblastoma

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 30, 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

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.49

Cadd

Benign

1.4

Dann

Benign

0.75

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