chr10-102599544-C-G

Variant names:

• chr10-102599544-C-G
• NM_016169.4:c.1022C>G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_016169.4(SUFU):​c.1022C>G​(p.Pro341Arg) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. 15/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SUFU NM_016169.4 missense, splice_region
• Scores: Splicing: ADA: 0.8702
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.63

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SUFU	NM_016169.4	c.1022C>G	p.Pro341Arg	missense_variant, splice_region_variant	Exon 8 of 12	ENST00000369902.8	NP_057253.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SUFU	ENST00000369902.8	c.1022C>G	p.Pro341Arg	missense_variant, splice_region_variant	Exon 8 of 12	1	NM_016169.4	ENSP00000358918.4
SUFU	ENST00000423559.2	c.1022C>G	p.Pro341Arg	missense_variant, splice_region_variant	Exon 8 of 10	1		ENSP00000411597.2
SUFU	ENST00000369899.6	c.1022C>G	p.Pro341Arg	missense_variant, splice_region_variant	Exon 8 of 11	1		ENSP00000358915.2
SUFU	ENST00000471000.1	n.*1C>G		downstream_gene_variant		5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Gorlin syndrome;C0025149:Medulloblastoma Uncertain:1

Sep 22, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. 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 tolerated. This variant has not been reported in the literature in individuals affected with SUFU-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 341 of the SUFU protein (p.Pro341Arg). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.0027	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.25	T;.;.
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.89	D;D;D
M_CAP	Benign	0.024	T
MetaRNN	Uncertain	0.54	D;D;D
MetaSVM	Benign	-0.68	T
MutationAssessor	Benign	0.69	N;N;N
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-1.3	N;N;N
REVEL	Benign	0.18
Sift	Benign	0.032	D;D;T
Sift4G	Benign	0.16	T;T;T
Polyphen		0.89	P;P;D
Vest4		0.60
MutPred		0.55		Gain of MoRF binding (P = 0.0255);Gain of MoRF binding (P = 0.0255);Gain of MoRF binding (P = 0.0255);
MVP		0.25
MPC		0.66
ClinPred		0.49	T
GERP RS		6.1
Varity_R		0.15
gMVP		0.50

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.87
dbscSNV1_RF	Benign	0.46
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr10-104359301;