rs587776578

chr10-102599545-G-Achr10-102599545-G-C

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PVS1 PM2 PP3_Strong PP5

The NM_016169.4(SUFU):c.1022+1G>A variant causes a splice donor change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,420 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: SUFU NM_016169.4 splice_donor
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:6 U:1
• Conservation: PhyloP100: 9.41

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 Pathogenic. Variant got 15 ACMG points.

• PVS1: Splicing variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 10-102599545-G-A is Pathogenic according to our data. Variant chr10-102599545-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 3571.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=4, Uncertain_significance=1}. Variant chr10-102599545-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SUFU	NM_016169.4	c.1022+1G>A		splice_donor_variant		ENST00000369902.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SUFU	ENST00000369902.8	c.1022+1G>A		splice_donor_variant		1	NM_016169.4	P1
SUFU	ENST00000369899.6	c.1022+1G>A		splice_donor_variant		1
SUFU	ENST00000423559.2	c.1022+1G>A		splice_donor_variant		1
SUFU	ENST00000471000.1			downstream_gene_variant		5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461420 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727006

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.00152 Hom.: 0

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:6 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Basal cell nevus syndrome 2 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jul 01, 2009

- -

SUFU-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Feb 12, 2019

The SUFU c.1022+1G>A variant is a splice donor variant that has been identified in a heterozygous state in a father and son who met criteria for nevoid basal cell carcinoma syndrome (NBCCS) and in a patient with desmoplastic medulloblastoma who did not have physical features of NBCCS at 23 months of age (Slade et al. 2007; Pastorino et al. 2009). This variant was also identified in a desmoplastic medulloblastoma sample from an individual who had a germline deletion encompassing the SUFU gene (Taylor et al. 2002). This variant was absent from 200 control alleles and is not found in the Genome Aggregation Database. RT-PCR demonstrated this splice donor variant results in a protein lacking exon 8 and produces a frameshift which leads to an early stop codon and truncation of the protein (Pastorino et al. 2009). Co-precipitation studies showed this variant was unable to bind GLI1 and GLI2 transcription factors and accumulated with these transcription factors in the nucleus, thereby preventing suppression of hedgehog signaling pathway target genes (Taylor et al. 2002). Based on the evidence, the c.1022+1G>A variant is classified as pathogenic for SUFU-related disorders. -

Gorlin syndrome;C0025149:Medulloblastoma Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jun 09, 2023

This sequence change affects a donor splice site in intron 8 of the SUFU gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product. This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. Studies have shown that disruption of this splice site results in skipping of exon 8 and introduces a premature termination codon (PMID: 12068298, 19533801). The resulting mRNA is expected to undergo nonsense-mediated decay. ClinVar contains an entry for this variant (Variation ID: 3571). This variant is also known as IVS8+1G>A. Disruption of this splice site has been observed in individual(s) with desmoplastic medulloblastoma and/or Gorlin syndrome (PMID: 19533801, 21188540). In at least one individual the variant was observed to be de novo. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Feb 09, 2022

Canonical splice site variant demonstrated to result in a null allele in a gene for which loss-of-function is a known mechanism of disease (Taylor et al., 2002, Pastorino et al., 2009); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25525159, 12068298, 19533801, 22508808, 22829011, 24217340, 15077159, 29725392, 29186568, 21188540) -

Medulloblastoma Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jul 01, 2009

- -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 16, 2020

The c.1022+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 8 of the SUFU gene. This alteration has been reported in an individual with sporadic desmoplastic medulloblastoma diagnosed at age 23 months (Slade I et al. Fam Cancer, 2011 Jun;10:337-42). In addition, this alteration was detected in a father and son with a clinical diagnosis of Gorlin syndrome, and was absent in both of the father's clinically unaffected parents. Parentage was not confirmed, and the alteration was assumed to be de novo (Pastorino L et al. Am J Med Genet A, 2009 Jul;149A:1539-43). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation. -

Gorlin syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Institute of Human Genetics, University of Leipzig Medical Center

May 31, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.36
Cadd	Pathogenic	33
Dann	Uncertain	0.99
Eigen	Pathogenic	1.3
Eigen_PC	Pathogenic	1.2
FATHMM_MKL	Pathogenic	0.98	D
MutationTaster	Benign	1.0	D;D;D
GERP RS		6.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
SpliceAI score (max)		0.98		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.98		Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs587776578; hg19: chr10-104359302; COSMIC: COSV64013745; COSMIC: COSV64013745;