rs761240106

chr10-102504217-C-Achr10-102504217-C-Gchr10-102504217-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_016169.4(SUFU):c.65C>A(p.Ala22Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 1,453,472 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A22G) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: SUFU NM_016169.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 2.39

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 2 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=0.32328853).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SUFU	NM_016169.4	c.65C>A	p.Ala22Asp	missense_variant	1/12	ENST00000369902.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SUFU	ENST00000369902.8	c.65C>A	p.Ala22Asp	missense_variant	1/12	1	NM_016169.4	P1
SUFU	ENST00000423559.2	c.65C>A	p.Ala22Asp	missense_variant	1/10	1
SUFU	ENST00000369899.6	c.65C>A	p.Ala22Asp	missense_variant	1/11	1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1453472 Hom.: 0 Cov.: 52 AF XY: 0.00000277 AC XY: 2 AN XY: 722796

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: 0.00000181

Gnomad4 OTH exome AF: 0.0000167

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Gorlin syndrome;C0025149:Medulloblastoma Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Oct 13, 2023

This sequence change replaces alanine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 22 of the SUFU protein (p.Ala22Asp). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with SUFU-related conditions. ClinVar contains an entry for this variant (Variation ID: 1010561). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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. -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 08, 2022

The p.A22D variant (also known as c.65C>A), located in coding exon 1 of the SUFU gene, results from a C to A substitution at nucleotide position 65. The alanine at codon 22 is replaced by aspartic acid, an amino acid with dissimilar properties. This amino acid position is conserved. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Benign	-0.090
Cadd	Uncertain	24
Dann	Uncertain	0.99
DEOGEN2	Benign	0.13	T;.;.
Eigen	Benign	0.14
Eigen_PC	Benign	0.17
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.84	T;T;T
M_CAP	Pathogenic	0.33	D
MetaRNN	Benign	0.32	T;T;T
MetaSVM	Benign	-0.76	T
MutationAssessor	Benign	0.69	N;N;N
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	0.070	N;N;N
REVEL	Benign	0.26
Sift	Benign	0.083	T;T;D
Sift4G	Benign	0.59	T;T;T
Polyphen		0.91	P;P;D
Vest4		0.27
MutPred		0.10		Loss of glycosylation at P24 (P = 0.0975);Loss of glycosylation at P24 (P = 0.0975);Loss of glycosylation at P24 (P = 0.0975);
MVP		0.36
MPC		1.6
ClinPred		0.84	D
GERP RS		4.9
Varity_R		0.44
gMVP		0.60

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: rs761240106; hg19: chr10-104263974;