10-102599540-G-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BS1 BS2

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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A340T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0063 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0073 (54 hom.)
• Consequence: SUFU NM_016169.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14 O:1
• Conservation: PhyloP100: 2.71

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 Benign. Variant got -19 ACMG points.

• PP2: Missense variant where missense usually causes diseases, SUFU
• 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 GnomAd at 953 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SUFU	NM_016169.4	c.1018G>T	p.Ala340Ser	missense_variant	8/12	ENST00000369902.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SUFU	ENST00000369902.8	c.1018G>T	p.Ala340Ser	missense_variant	8/12	1	NM_016169.4	P1
SUFU	ENST00000423559.2	c.1018G>T	p.Ala340Ser	missense_variant	8/10	1
SUFU	ENST00000369899.6	c.1018G>T	p.Ala340Ser	missense_variant	8/11	1
SUFU	ENST00000471000.1	n.800G>T		non_coding_transcript_exon_variant	6/6	5

Frequencies

GnomAD3 genomes AF: 0.00626 AC: 953 AN: 152196 Hom.: 3 Cov.: 32

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.: 8 AF XY: 0.00580 AC XY: 788 AN XY: 135758

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.: 54 Cov.: 31 AF XY: 0.00713 AC XY: 5185 AN XY: 727110

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.: 3 Cov.: 32 AF XY: 0.00623 AC XY: 464 AN XY: 74478

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.: 5

Bravo AF: 0.00560

TwinsUK AF: 0.00836 AC: 31

ALSPAC AF: 0.00701 AC: 27

ESP6500AA AF: 0.00136 AC: 6

ESP6500EA AF: 0.00942 AC: 81

ExAC AF: 0.00605 AC: 734

EpiCase AF: 0.0118

EpiControl AF: 0.00818

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:14 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:8

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Sep 27, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	SUFU: BP4, BS2 -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jun 30, 2022	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Aug 25, 2023	- -
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) -
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	-	- -
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. -

not specified Benign:2 Other:1

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
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

Invitae

Feb 01, 2024

- -

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. -

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

- -

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	T
BayesDel_noAF	Benign	-0.40
Cadd	Benign	15
Dann	Benign	0.85
DEOGEN2	Benign	0.12	T;.;.
Eigen	Benign	-0.60
Eigen_PC	Benign	-0.38
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.87	D;D;D
MetaRNN	Benign	0.0075	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.34	N;N;N
MutationTaster	Benign	0.94	D;D;D
PrimateAI	Benign	0.30	T
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	T
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

Other links and lift over

dbSNP: rs34135067; hg19: chr10-104359297; COSMIC: COSV64014005;