rs12780580

Positions:

• chr10-102504202-C-A
• chr10-102504202-C-T

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.50C>A​(p.Ala17Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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 (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: SUFU NM_016169.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.53

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=0.1749385).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SUFU	NM_016169.4	c.50C>A	p.Ala17Asp	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.50C>A	p.Ala17Asp	missense_variant	1/12	1	NM_016169.4	ENSP00000358918	P1
SUFU	ENST00000423559.2	c.50C>A	p.Ala17Asp	missense_variant	1/10	1		ENSP00000411597
SUFU	ENST00000369899.6	c.50C>A	p.Ala17Asp	missense_variant	1/11	1		ENSP00000358915

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 49

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Uncertain	0.066	T
BayesDel_noAF	Benign	-0.14
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.14	T;.;.
Eigen	Benign	-0.033
Eigen_PC	Benign	0.068
FATHMM_MKL	Benign	0.63	D
LIST_S2	Uncertain	0.86	D;D;D
M_CAP	Pathogenic	0.38	D
MetaRNN	Benign	0.17	T;T;T
MetaSVM	Benign	-0.76	T
MutationAssessor	Benign	0.0	N;N;N
MutationTaster	Benign	0.99	D;D;D
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	0.20	N;N;N
REVEL	Benign	0.12
Sift	Uncertain	0.010	D;D;D
Sift4G	Benign	0.22	T;T;T
Polyphen		0.18	B;B;P
Vest4		0.33
MutPred		0.092		Loss of glycosylation at P16 (P = 0.1786);Loss of glycosylation at P16 (P = 0.1786);Loss of glycosylation at P16 (P = 0.1786);
MVP		0.26
MPC		1.6
ClinPred		0.83	D
GERP RS		4.4
Varity_R		0.38
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: rs12780580; hg19: chr10-104263959;