NM_016169.4:c.865C>G

Variant names:

• chr10-102597248-C-G
• rs755961394
• NM_016169.4:c.865C>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_016169.4(SUFU):​c.865C>G​(p.Arg289Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. R289Q) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SUFU NM_016169.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.40
• Publications: 0 publications found

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]

SUFU Gene-Disease associations (from GenCC):

• medulloblastoma

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen
• nevoid basal cell carcinoma syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Illumina, Genomics England PanelApp
• basal cell nevus syndrome 2

  Inheritance: AD Classification: STRONG Submitted by: G2P
• ocular motor apraxia, Cogan type

  Inheritance: AD Classification: STRONG Submitted by: Franklin by Genoox
• Joubert syndrome 32

  Inheritance: AR Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• Joubert syndrome

  Inheritance: AR, AD Classification: MODERATE, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics
• apraxia

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• ciliopathy

  Inheritance: AR Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016169.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SUFU	NM_016169.4	MANE Select	c.865C>G	p.Arg289Gly	missense	Exon 7 of 12	NP_057253.2
	SUFU	NM_001178133.2		c.865C>G	p.Arg289Gly	missense	Exon 7 of 11	NP_001171604.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SUFU	ENST00000369902.8	TSL:1 MANE Select	c.865C>G	p.Arg289Gly	missense	Exon 7 of 12	ENSP00000358918.4
	SUFU	ENST00000423559.2	TSL:1	c.865C>G	p.Arg289Gly	missense	Exon 7 of 10	ENSP00000411597.2
	SUFU	ENST00000369899.6	TSL:1	c.865C>G	p.Arg289Gly	missense	Exon 7 of 11	ENSP00000358915.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Gorlin syndrome;C0025149:Medulloblastoma (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.43
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.060
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.11	T
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Benign	0.041	D
MetaRNN	Uncertain	0.70	D
MetaSVM	Benign	-0.80	T
MutationAssessor	Benign	1.4	L
PhyloP100		1.4
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-0.14	N
REVEL	Benign	0.29
Sift	Benign	0.27	T
Sift4G	Benign	0.42	T
Polyphen		0.99	D
Vest4		0.81
MutPred		0.53		Gain of glycosylation at S288 (P = 0.0255)
MVP		0.72
MPC		1.3
ClinPred		0.91	D
GERP RS		4.0
Varity_R		0.26
gMVP		0.64
Mutation Taster		=14/86	disease causing

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

Other links and lift over

dbSNP: rs755961394; hg19: chr10-104357005;