rs587776578

Variant names:

• chr10-102599545-G-A
• rs587776578
• NM_016169.4:c.1022+1G>A

Your query was ambiguous. Multiple possible variants found:

• chr10-102599545-G-A
• chr10-102599545-G-C

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_016169.4(SUFU):​c.1022+1G>A variant causes a splice donor, intron 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 Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: SUFU NM_016169.4 splice_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 9.41
• Publications: 5 publications found

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 Gene-Disease associations (from GenCC):

• medulloblastoma

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen
• nevoid basal cell carcinoma syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Illumina, Genomics England PanelApp
• basal cell nevus syndrome 2

  Inheritance: AD Classification: STRONG Submitted by: G2P
• ocular motor apraxia, Cogan type

  Inheritance: AD Classification: STRONG Submitted by: Franklin by Genoox
• Joubert syndrome 32

  Inheritance: AR Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• Joubert syndrome

  Inheritance: AR, AD Classification: MODERATE, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics
• apraxia

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• ciliopathy

  Inheritance: AR Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) 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
• PP5: Variant 10-102599545-G-A is Pathogenic according to our data. Variant chr10-102599545-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 3571.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SUFU	NM_016169.4	c.1022+1G>A		splice_donor_variant, intron_variant	Intron 8 of 11	ENST00000369902.8	NP_057253.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SUFU	ENST00000369902.8	c.1022+1G>A		splice_donor_variant, intron_variant	Intron 8 of 11	1	NM_016169.4	ENSP00000358918.4
SUFU	ENST00000423559.2	c.1022+1G>A		splice_donor_variant, intron_variant	Intron 8 of 9	1		ENSP00000411597.2
SUFU	ENST00000369899.6	c.1022+1G>A		splice_donor_variant, intron_variant	Intron 8 of 10	1		ENSP00000358915.2
SUFU	ENST00000471000.1	n.*2G>A		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

African (AFR) AF: 0.00 AC: 0 AN: 33470

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53360

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111664

Other (OTH) AF: 0.00 AC: 0 AN: 60362

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000716 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Basal cell nevus syndrome 2 Pathogenic:1

Jul 01, 2009

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

SUFU-related disorder Pathogenic:1

Feb 12, 2019

Illumina Laboratory Services, Illumina

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jul 22, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 altered protein product. This variant is not present in population databases (gnomAD no frequency). 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. This variant is also known as IVS8+1G>A. ClinVar contains an entry for this variant (Variation ID: 3571). Studies have shown that disruption of this splice site results in skipping of exon 8, and produces a non-functional protein and/or introduces a premature termination codon (PMID: 12068298, 19533801; Invitae). For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:1

Jun 25, 2025

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 (TPMID: 12068298, 19533801); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25525159, 19533801, 22508808, 22829011, 24217340, 15077159, 29725392, 29186568, 21188540, 34675124, 36497448, 36313636, 12068298) -

Medulloblastoma Pathogenic:1

Jul 01, 2009

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Hereditary cancer-predisposing syndrome Pathogenic:1

Nov 16, 2020

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

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
PhyloP100		9.4
GERP RS		6.1
Mutation Taster		=0/100	disease causing (ClinVar)

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

Other links and lift over

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