10-102504171-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.19A>G(p.Ser7Gly) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S7R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SUFU NM_016169.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.99

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 where missense usually causes diseases, SUFU
• BP4: Computational evidence support a benign effect (MetaRNN=0.14584237).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SUFU	NM_016169.4	c.19A>G	p.Ser7Gly	missense_variant	1/12	ENST00000369902.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SUFU	ENST00000369902.8	c.19A>G	p.Ser7Gly	missense_variant	1/12	1	NM_016169.4	P1
SUFU	ENST00000423559.2	c.19A>G	p.Ser7Gly	missense_variant	1/10	1
SUFU	ENST00000369899.6	c.19A>G	p.Ser7Gly	missense_variant	1/11	1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1394678 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 688048

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

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

Invitae

Jul 01, 2021

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. 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. This variant has not been reported in the literature in individuals affected with SUFU-related conditions. This sequence change replaces serine with glycine at codon 7 of the SUFU protein (p.Ser7Gly). The serine residue is moderately conserved and there is a small physicochemical difference between serine and glycine. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the ExAC database. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.42
Cadd	Uncertain	24
Dann	Uncertain	0.99
DEOGEN2	Benign	0.16	T;.;.
Eigen	Benign	-0.17
Eigen_PC	Benign	0.032
FATHMM_MKL	Benign	0.72	D
LIST_S2	Benign	0.85	T;T;T
M_CAP	Pathogenic	0.33	D
MetaRNN	Benign	0.15	T;T;T
MetaSVM	Benign	-0.84	T
MutationAssessor	Benign	0.90	L;L;L
MutationTaster	Benign	0.63	D;D;D
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-0.18	N;N;N
REVEL	Benign	0.091
Sift	Pathogenic	0.0	D;D;D
Sift4G	Benign	0.52	T;T;T
Polyphen		0.0	B;B;B
Vest4		0.11
MutPred		0.17		Loss of glycosylation at S7 (P = 2e-04);Loss of glycosylation at S7 (P = 2e-04);Loss of glycosylation at S7 (P = 2e-04);
MVP		0.45
MPC		0.68
ClinPred		0.73	D
GERP RS		5.2
Varity_R		0.39
gMVP		0.37

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: rs2062288510; hg19: chr10-104263928;