rs189234140

Positions:

• chr10-102504164-G-A

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_016169.4(SUFU):​c.12G>A​(p.Leu4=) variant causes a synonymous change. The variant allele was found at a frequency of 0.000737 in 1,544,724 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0039 (6 hom., cov: 33)
  • Exomes 𝑓: 0.00040 (0 hom.)
• Consequence: SUFU NM_016169.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 5.52

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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.43).
• BP6: Variant 10-102504164-G-A is Benign according to our data. Variant chr10-102504164-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 241081.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-102504164-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00386 (587/152208) while in subpopulation AFR AF= 0.0135 (560/41538). AF 95% confidence interval is 0.0126. There are 6 homozygotes in gnomad4. There are 250 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 587 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SUFU	NM_016169.4	c.12G>A	p.Leu4=	synonymous_variant	1/12	ENST00000369902.8	NP_057253.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SUFU	ENST00000369902.8	c.12G>A	p.Leu4=	synonymous_variant	1/12	1	NM_016169.4	ENSP00000358918	P1
SUFU	ENST00000423559.2	c.12G>A	p.Leu4=	synonymous_variant	1/10	1		ENSP00000411597
SUFU	ENST00000369899.6	c.12G>A	p.Leu4=	synonymous_variant	1/11	1		ENSP00000358915

Frequencies

GnomAD3 genomes AF: 0.00383 AC: 582 AN: 152100 Hom.: 5 Cov.: 33

Gnomad AFR AF: 0.0134

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00105

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.000905 AC: 132 AN: 145936 Hom.: 0 AF XY: 0.000743 AC XY: 59 AN XY: 79380

Gnomad AFR exome AF: 0.0150

Gnomad AMR exome AF: 0.000855

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000545

Gnomad OTH exome AF: 0.000240

GnomAD4 exome AF: 0.000396 AC: 552 AN: 1392516 Hom.: 0 Cov.: 31 AF XY: 0.000361 AC XY: 248 AN XY: 686926

Gnomad4 AFR exome AF: 0.0135

Gnomad4 AMR exome AF: 0.00132

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000379

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000167

Gnomad4 OTH exome AF: 0.000884

GnomAD4 genome AF: 0.00386 AC: 587 AN: 152208 Hom.: 6 Cov.: 33 AF XY: 0.00336 AC XY: 250 AN XY: 74406

Gnomad4 AFR AF: 0.0135

Gnomad4 AMR AF: 0.00105

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.000412 Hom.: 0

Bravo AF: 0.00456

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 26, 2021	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	SUFU: BP4, BS1, BS2 -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 19, 2018	Variant summary: SUFU c.12G>A alters a conserved nucleotide resulting in a synonymous change. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0015 in 171858 control chromosomes in the gnomAD database, including 1 homozygotes. The observed variant frequency is approximately 1460-fold higher than the estimated maximal expected allele frequency for a pathogenic variant in SUFU causing Nevoid Basal Cell Carcinoma Syndrome (Gorlin Syndrome) phenotype (1e-06), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.12G>A in individuals affected with Nevoid Basal Cell Carcinoma Syndrome (Gorlin Syndrome) and no experimental evidence demonstrating its impact on protein function have been reported. Three ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant twice as likely benign/benign and once as uncertain significance. Based on the evidence outlined above, the variant was classified as benign. -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jun 04, 2021	- -

Gorlin syndrome;C0025149:Medulloblastoma Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Medulloblastoma Benign:1

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

Hereditary cancer-predisposing syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 08, 2017

This alteration is classified as likely 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
BayesDel_noAF	Benign	-0.43
CADD	Benign	14
DANN	Benign	0.97

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: rs189234140; hg19: chr10-104263921;