rs2298278

chr10-102630546-A-Gchr10-102630546-A-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_016169.4(SUFU):c.*391A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.15 in 400,716 control chromosomes in the GnomAD database, including 6,502 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.15 (2263 hom., cov: 33)
  • Exomes 𝑓: 0.15 (4239 hom.)
• Consequence: SUFU NM_016169.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.871

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 10-102630546-A-G is Benign according to our data. Variant chr10-102630546-A-G is described in ClinVar as [Benign]. Clinvar id is 298581.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.4 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SUFU	NM_016169.4	c.*391A>G		3_prime_UTR_variant	12/12	ENST00000369902.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SUFU	ENST00000369902.8	c.*391A>G		3_prime_UTR_variant	12/12	1	NM_016169.4	P1

Frequencies

GnomAD3 genomes AF: 0.152 AC: 23088 AN: 152104 Hom.: 2255 Cov.: 33

Gnomad AFR AF: 0.218

Gnomad AMI AF: 0.122

Gnomad AMR AF: 0.194

Gnomad ASJ AF: 0.0642

Gnomad EAS AF: 0.415

Gnomad SAS AF: 0.222

Gnomad FIN AF: 0.0727

Gnomad MID AF: 0.0791

Gnomad NFE AF: 0.0939

Gnomad OTH AF: 0.163

GnomAD4 exome AF: 0.148 AC: 36803 AN: 248492 Hom.: 4239 Cov.: 0 AF XY: 0.153 AC XY: 19457 AN XY: 126968

Gnomad4 AFR exome AF: 0.222

Gnomad4 AMR exome AF: 0.232

Gnomad4 ASJ exome AF: 0.0681

Gnomad4 EAS exome AF: 0.449

Gnomad4 SAS exome AF: 0.234

Gnomad4 FIN exome AF: 0.0792

Gnomad4 NFE exome AF: 0.0892

Gnomad4 OTH exome AF: 0.123

GnomAD4 genome AF: 0.152 AC: 23132 AN: 152224 Hom.: 2263 Cov.: 33 AF XY: 0.155 AC XY: 11509 AN XY: 74428

Gnomad4 AFR AF: 0.218

Gnomad4 AMR AF: 0.195

Gnomad4 ASJ AF: 0.0642

Gnomad4 EAS AF: 0.414

Gnomad4 SAS AF: 0.222

Gnomad4 FIN AF: 0.0727

Gnomad4 NFE AF: 0.0939

Gnomad4 OTH AF: 0.166

Alfa AF: 0.125 Hom.: 717

Bravo AF: 0.167

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Medulloblastoma Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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 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 v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
Cadd	Benign	0.84
Dann	Benign	0.31

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: rs2298278; hg19: chr10-104390303; COSMIC: COSV64019008;