10-102504160-A-G

Position:

• chr10-102504160-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_016169.4(SUFU):​c.8A>G​(p.Glu3Gly) variant causes a missense change. The variant allele was found at a frequency of 0.000000719 in 1,391,722 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: SUFU NM_016169.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.95

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), SUFU. . Gene score misZ 1.9341 (greater than the threshold 3.09). Trascript score misZ 3.1202 (greater than threshold 3.09). GenCC has associacion of gene with apraxia, ciliopathy, ocular motor apraxia, Cogan type, nevoid basal cell carcinoma syndrome, Joubert syndrome, Joubert syndrome 32, medulloblastoma.
• BP4: Computational evidence support a benign effect (MetaRNN=0.13899916).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SUFU	NM_016169.4	c.8A>G	p.Glu3Gly	missense_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.8A>G	p.Glu3Gly	missense_variant	1/12	1	NM_016169.4	ENSP00000358918	P1
SUFU	ENST00000423559.2	c.8A>G	p.Glu3Gly	missense_variant	1/10	1		ENSP00000411597
SUFU	ENST00000369899.6	c.8A>G	p.Glu3Gly	missense_variant	1/11	1		ENSP00000358915

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.19e-7 AC: 1 AN: 1391722 Hom.: 0 Cov.: 31 AF XY: 0.00000146 AC XY: 1 AN XY: 686654

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: 9.27e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Alfa AF: 0.000111 Hom.: 0

ExAC AF: 0.0000110 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Gorlin syndrome;C0025149:Medulloblastoma Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Apr 20, 2018

This sequence change replaces glutamic acid with glycine at codon 3 of the SUFU protein (p.Glu3Gly). The glutamic acid residue is highly conserved and there is a moderate physicochemical difference between glutamic acid and glycine. While this variant is present in population databases (rs757097388), the frequency information is unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has not been reported in the literature in individuals with SUFU-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.070	T
BayesDel_noAF	Benign	-0.34
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.17	T;.;.
Eigen	Benign	-0.12
Eigen_PC	Benign	0.078
FATHMM_MKL	Benign	0.57	D
LIST_S2	Benign	0.84	T;T;T
M_CAP	Pathogenic	0.55	D
MetaRNN	Benign	0.14	T;T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	0.69	N;N;N
MutationTaster	Benign	0.99	D;D;D
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-0.070	N;N;N
REVEL	Benign	0.094
Sift	Pathogenic	0.0	D;D;D
Sift4G	Benign	0.21	T;T;T
Polyphen		0.0	B;B;B
Vest4		0.18
MutPred		0.22		Loss of sheet (P = 0.0228);Loss of sheet (P = 0.0228);Loss of sheet (P = 0.0228);
MVP		0.24
MPC		1.1
ClinPred		0.63	D
GERP RS		5.3
Varity_R		0.48
gMVP		0.65

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: rs757097388; hg19: chr10-104263917;