10-102594059-C-G

Variant names:

• chr10-102594059-C-G
• rs1235137905
• NM_016169.4:c.750C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_016169.4(SUFU):​c.750C>G​(p.His250Gln) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H250R) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SUFU NM_016169.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.111
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15326959).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SUFU	NM_016169.4	c.750C>G	p.His250Gln	missense_variant	Exon 6 of 12	ENST00000369902.8	NP_057253.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SUFU	ENST00000369902.8	c.750C>G	p.His250Gln	missense_variant	Exon 6 of 12	1	NM_016169.4	ENSP00000358918.4
SUFU	ENST00000423559.2	c.750C>G	p.His250Gln	missense_variant	Exon 6 of 10	1		ENSP00000411597.2
SUFU	ENST00000369899.6	c.750C>G	p.His250Gln	missense_variant	Exon 6 of 11	1		ENSP00000358915.2
SUFU	ENST00000471000.1	n.532C>G		non_coding_transcript_exon_variant	Exon 4 of 6	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.070
CADD	Benign	20
DANN	Benign	0.96
DEOGEN2	Benign	0.14	T;.;.
Eigen	Benign	-0.45
Eigen_PC	Benign	-0.29
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.74	T;T;T
M_CAP	Benign	0.032	D
MetaRNN	Benign	0.15	T;T;T
MetaSVM	Benign	-0.80	T
MutationAssessor	Benign	-0.69	N;N;N
PhyloP100		0.11
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-0.33	N;N;N
REVEL	Uncertain	0.41
Sift	Benign	0.34	T;T;T
Sift4G	Benign	0.53	T;T;T
Polyphen		0.0	B;B;B
Vest4		0.20
MutPred		0.34		Gain of disorder (P = 0.1621);Gain of disorder (P = 0.1621);Gain of disorder (P = 0.1621);
MVP		0.92
MPC		0.61
ClinPred		0.31	T
GERP RS		1.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.41
gMVP		0.50
Mutation Taster		=31/69	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs1235137905; hg19: chr10-104353816;