NM_016169.4:c.848A>G

Variant names:

• chr10-102597231-A-G
• rs763598499
• NM_016169.4:c.848A>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4 BP6

The NM_016169.4(SUFU):​c.848A>G​(p.Glu283Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000185 in 1,461,826 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E283A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000018 (0 hom.)
• Consequence: SUFU NM_016169.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 8.95
• 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: ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• nevoid basal cell carcinoma syndrome

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

  Inheritance: AD Classification: STRONG Submitted by: G2P
• neurodevelopmental disorder

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

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

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

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

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

  Inheritance: AR Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.38696274).
• BP6: Variant 10-102597231-A-G is Benign according to our data. Variant chr10-102597231-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 582319.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SUFU	NM_016169.4	MANE Select	c.848A>G	p.Glu283Gly	missense	Exon 7 of 12	NP_057253.2
	SUFU	NM_001178133.2		c.848A>G	p.Glu283Gly	missense	Exon 7 of 11	NP_001171604.1	Q9UMX1-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SUFU	ENST00000369902.8	TSL:1 MANE Select	c.848A>G	p.Glu283Gly	missense	Exon 7 of 12	ENSP00000358918.4	Q9UMX1-1
	SUFU	ENST00000423559.2	TSL:1	c.848A>G	p.Glu283Gly	missense	Exon 7 of 10	ENSP00000411597.2	Q9UMX1-3
	SUFU	ENST00000369899.6	TSL:1	c.848A>G	p.Glu283Gly	missense	Exon 7 of 11	ENSP00000358915.2	Q9UMX1-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000795 AC: 2 AN: 251430 AF XY: 0.0000147

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000185 AC: 27 AN: 1461826 Hom.: 0 Cov.: 32 AF XY: 0.0000248 AC XY: 18 AN XY: 727214

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53370

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.0000243 AC: 27 AN: 1112004

Other (OTH) AF: 0.00 AC: 0 AN: 60388

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000308 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	-	Familial meningioma (1)
-	1	-	Gorlin syndrome;C0025149:Medulloblastoma (1)
-	-	1	Hereditary cancer-predisposing syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Uncertain	0.058	T
BayesDel_noAF	Benign	-0.14
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.19	T
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	D
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.39	T
MetaSVM	Benign	-0.80	T
MutationAssessor	Benign	1.4	L
PhyloP100		8.9
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-0.89	N
REVEL	Benign	0.17
Sift	Benign	0.10	T
Sift4G	Benign	0.18	T
Polyphen		0.99	D
Vest4		0.69
MutPred		0.35		Loss of solvent accessibility (P = 0.0387)
MVP		0.25
MPC		0.80
ClinPred		0.59	D
GERP RS		6.0
Varity_R		0.11
gMVP		0.62
Mutation Taster		=10/90	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: rs763598499; hg19: chr10-104356988;