10-102599540-G-T

Position:

chr10-102599540-G-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBS1BS2

The NM_016169.4(SUFU):c.1018G>T(p.Ala340Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00718 in 1,613,966 control chromosomes in the GnomAD database, including 57 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0063 ( 3 hom., cov: 32)

Exomes 𝑓: 0.0073 ( 54 hom. )

Consequence

SUFU
NM_016169.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14O:1

Conservation

PhyloP100: 2.71

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:

SUFU (HGNC:):

SUFU links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 ACMG points.

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.

BP4

Computational evidence support a benign effect (MetaRNN=0.007463455).

BP6

Variant 10-102599540-G-T is Benign according to our data. Variant chr10-102599540-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 135282.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-102599540-G-T is described in Lovd as [Benign]. Variant chr10-102599540-G-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00626 (953/152314) while in subpopulation NFE AF= 0.0101 (686/68028). AF 95% confidence interval is 0.00946. There are 3 homozygotes in gnomad4. There are 464 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 953 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SUFU	NM_016169.4 linkuse as main transcript	c.1018G>T	p.Ala340Ser	missense_variant	8/12	ENST00000369902.8	NP_057253.2	Q9UMX1-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
SUFU	ENST00000369902.8 linkuse as main transcript	c.1018G>T	p.Ala340Ser	missense_variant	8/12	1	NM_016169.4	ENSP00000358918.4	Q9UMX1-1
SUFU	ENST00000423559.2 linkuse as main transcript	c.1018G>T	p.Ala340Ser	missense_variant	8/10	1		ENSP00000411597.2	Q9UMX1-3
SUFU	ENST00000369899.6 linkuse as main transcript	c.1018G>T	p.Ala340Ser	missense_variant	8/11	1		ENSP00000358915.2	Q9UMX1-2
SUFU	ENST00000471000.1 linkuse as main transcript	n.800G>T		non_coding_transcript_exon_variant	6/6	5

Frequencies

GnomAD3 genomes

AF:

0.00626

AC:

953

AN:

152196

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00145

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.00667

Gnomad ASJ

AF:

0.00202

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00763

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0101

Gnomad OTH

AF:

0.00623

GnomAD3 exomes

AF:

0.00596

AC:

1496

AN:

251160

Hom.:

AF XY:

0.00580

AC XY:

788

AN XY:

135758

show subpopulations

Gnomad AFR exome

AF:

0.000862

Gnomad AMR exome

AF:

0.00370

Gnomad ASJ exome

AF:

0.00189

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000359

Gnomad FIN exome

AF:

0.00782

Gnomad NFE exome

AF:

0.00984

Gnomad OTH exome

AF:

0.00620

GnomAD4 exome

AF:

0.00727

AC:

10630

AN:

1461652

Hom.:

Cov.:

AF XY:

0.00713

AC XY:

5185

AN XY:

727110

show subpopulations

Gnomad4 AFR exome

AF:

0.00128

Gnomad4 AMR exome

AF:

0.00382

Gnomad4 ASJ exome

AF:

0.00195

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000290

Gnomad4 FIN exome

AF:

0.00856

Gnomad4 NFE exome

AF:

0.00849

Gnomad4 OTH exome

AF:

0.00719

GnomAD4 genome

AF:

0.00626

AC:

953

AN:

152314

Hom.:

Cov.:

AF XY:

0.00623

AC XY:

464

AN XY:

74478

show subpopulations

Gnomad4 AFR

AF:

0.00144

Gnomad4 AMR

AF:

0.00666

Gnomad4 ASJ

AF:

0.00202

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000415

Gnomad4 FIN

AF:

0.00763

Gnomad4 NFE

AF:

0.0101

Gnomad4 OTH

AF:

0.00616

Alfa

AF:

0.00824

Hom.:

Bravo

AF:

0.00560

TwinsUK

AF:

0.00836

AC:

ALSPAC

AF:

0.00701

AC:

ESP6500AA

AF:

0.00136

AC:

ESP6500EA

AF:

0.00942

AC:

ExAC

AF:

0.00605

AC:

734

EpiCase

AF:

0.0118

EpiControl

AF:

0.00818

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:14Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:8

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	SUFU: BP4, BS2 -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 25, 2016	Variant summary: The SUFU c.1018G>T (p.Ala340Ser) variant involves the alteration of a conserved nucleotide. 4/5 in silico tools predict a benign outcome. This variant was found in 733/120930 control chromosomes (including 5 homozygotes), predominantly observed in the European (Finnish) subpopulation at a frequency of 0.0105836 (70/6614). This frequency is about 10499 times the estimated maximal expected allele frequency of a pathogenic SUFU variant (0.000001), suggesting this is a benign polymorphism found primarily in the populations of European (Finnish) origin. Taken together, this variant is classified as Benign. -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Aug 25, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Sep 27, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jun 30, 2022	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 15, 2020	This variant is associated with the following publications: (PMID: 16760173, 28717660, 24728327, 12068298, 21188540, 17102621, 22508808, 28051113) -

not specified

Benign:2Other:1

not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Gorlin syndrome;C0025149:Medulloblastoma

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Gorlin syndrome;C0025149:Medulloblastoma;C3551915:Familial meningioma;C4540342:Joubert syndrome 32

Benign:1

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jul 26, 2021

- -

Medulloblastoma

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Hereditary cancer-predisposing syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 08, 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

AlphaMissense

Benign

0.069

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.40

CADD

Benign

DANN

Benign

0.85

DEOGEN2

Benign

0.12

T;.;.

Eigen

Benign

-0.60

Eigen_PC

Benign

-0.38

FATHMM_MKL

Uncertain

0.85

LIST_S2

Uncertain

0.87

D;D;D

MetaRNN

Benign

0.0075

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.34

N;N;N

PrimateAI

Benign

0.30

PROVEAN

Benign

0.31

N;N;N

REVEL

Benign

0.044

Sift

Benign

0.98

T;T;T

Sift4G

Benign

0.84

T;T;T

Polyphen

0.15

B;B;B

Vest4

0.50

MVP

0.47

MPC

0.59

ClinPred

0.0074

GERP RS

3.3

Varity_R

0.023

gMVP

0.32

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