NM_016169.4:c.1299T>C

Variant names:

• chr10-102627177-T-C
• rs17114803
• NM_016169.4:c.1299T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_016169.4(SUFU):​c.1299T>C​(p.Ile433Ile) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.114 in 1,613,514 control chromosomes in the GnomAD database, including 15,918 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 Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.15 (2263 hom., cov: 32)
  • Exomes 𝑓: 0.11 (13655 hom.)
• Consequence: SUFU NM_016169.4 splice_region, synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.661
• Publications: 38 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: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BP6: Variant 10-102627177-T-C is Benign according to our data. Variant chr10-102627177-T-C is described in ClinVar as Benign. ClinVar VariationId is 260687.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.661 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.401 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016169.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SUFU	NM_016169.4	MANE Select	c.1299T>C	p.Ile433Ile	splice_region synonymous	Exon 11 of 12	NP_057253.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SUFU	ENST00000369902.8	TSL:1 MANE Select	c.1299T>C	p.Ile433Ile	splice_region synonymous	Exon 11 of 12	ENSP00000358918.4

Frequencies

GnomAD3 genomes AF: 0.151 AC: 23040 AN: 152144 Hom.: 2255 Cov.: 32

Gnomad AFR AF: 0.219

Gnomad AMI AF: 0.122

Gnomad AMR AF: 0.193

Gnomad ASJ AF: 0.0643

Gnomad EAS AF: 0.416

Gnomad SAS AF: 0.222

Gnomad FIN AF: 0.0725

Gnomad MID AF: 0.0823

Gnomad NFE AF: 0.0931

Gnomad OTH AF: 0.163

GnomAD2 exomes AF: 0.160 AC: 40291 AN: 251478 AF XY: 0.155

Gnomad AFR exome AF: 0.224

Gnomad AMR exome AF: 0.267

Gnomad ASJ exome AF: 0.0715

Gnomad EAS exome AF: 0.413

Gnomad FIN exome AF: 0.0745

Gnomad NFE exome AF: 0.0863

Gnomad OTH exome AF: 0.124

GnomAD4 exome AF: 0.111 AC: 161590 AN: 1461254 Hom.: 13655 Cov.: 32 AF XY: 0.113 AC XY: 82193 AN XY: 726982

African (AFR) AF: 0.221 AC: 7384 AN: 33448

American (AMR) AF: 0.261 AC: 11682 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0679 AC: 1775 AN: 26136

East Asian (EAS) AF: 0.447 AC: 17727 AN: 39694

South Asian (SAS) AF: 0.226 AC: 19495 AN: 86228

European-Finnish (FIN) AF: 0.0753 AC: 4021 AN: 53398

Middle Eastern (MID) AF: 0.112 AC: 644 AN: 5766

European-Non Finnish (NFE) AF: 0.0823 AC: 91433 AN: 1111496

Other (OTH) AF: 0.123 AC: 7429 AN: 60368

GnomAD4 genome AF: 0.152 AC: 23084 AN: 152260 Hom.: 2263 Cov.: 32 AF XY: 0.154 AC XY: 11484 AN XY: 74450

African (AFR) AF: 0.219 AC: 9079 AN: 41550

American (AMR) AF: 0.194 AC: 2967 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.0643 AC: 223 AN: 3470

East Asian (EAS) AF: 0.416 AC: 2153 AN: 5174

South Asian (SAS) AF: 0.222 AC: 1072 AN: 4824

European-Finnish (FIN) AF: 0.0725 AC: 769 AN: 10614

Middle Eastern (MID) AF: 0.0850 AC: 25 AN: 294

European-Non Finnish (NFE) AF: 0.0931 AC: 6334 AN: 68020

Other (OTH) AF: 0.166 AC: 351 AN: 2114

Alfa AF: 0.116 Hom.: 4526

Bravo AF: 0.166

Asia WGS AF: 0.314 AC: 1086 AN: 3478

EpiCase AF: 0.0887

EpiControl AF: 0.0870

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Aug 31, 2016

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The SUFU c.1299T>C (p.Ile433Ile) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. One in silico tool predicts a polymorphism outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing. ESE finder predicts that this variant may affect ESE site of SC35. However, these predictions have yet to be confirmed by functional studies. This variant was found in 19257/121358 control chromosomes (2233 homozygotes) at a frequency of 0.1586793, which is significantly higher than the estimated maximal expected allele frequency of a pathogenic SUFU variant (0.000001), suggesting this variant is likely a benign polymorphism. Taken together, this variant is classified as benign.

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Hereditary cancer-predisposing syndrome Benign:2

Dec 09, 2016

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Dec 19, 2024

Hereditary Cancer Laboratory, Hospital Universitario 12 de Octubre

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

BA1

not specified Benign:1

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Gorlin syndrome;C0025149:Medulloblastoma Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Familial meningioma Benign:1

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Medulloblastoma Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	12
DANN	Benign	0.63
PhyloP100		0.66
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

dbSNP: rs17114803; hg19: chr10-104386934; COSMIC: COSV64017293;