rs757097388

Variant names:

• chr10-102504160-A-G
• rs757097388
• NM_016169.4:c.8A>G

Your query was ambiguous. Multiple possible variants found:

• chr10-102504160-A-G
• chr10-102504160-A-C
• chr10-102504160-A-T

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.8A>G​(p.Glu3Gly) variant causes a missense change. The variant allele was found at a frequency of 0.000000719 in 1,391,722 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E3D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: SUFU NM_016169.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.95
• 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: 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=0.13899916).

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.8A>G	p.Glu3Gly	missense	Exon 1 of 12	NP_057253.2
	SUFU	NM_001178133.2		c.8A>G	p.Glu3Gly	missense	Exon 1 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.8A>G	p.Glu3Gly	missense	Exon 1 of 12	ENSP00000358918.4	Q9UMX1-1
	SUFU	ENST00000423559.2	TSL:1	c.8A>G	p.Glu3Gly	missense	Exon 1 of 10	ENSP00000411597.2	Q9UMX1-3
	SUFU	ENST00000369899.6	TSL:1	c.8A>G	p.Glu3Gly	missense	Exon 1 of 11	ENSP00000358915.2	Q9UMX1-2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000685 AC: 1 AN: 145952 AF XY: 0.0000126

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: 0.0000181

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 7.19e-7 AC: 1 AN: 1391722 Hom.: 0 Cov.: 31 AF XY: 0.00000146 AC XY: 1 AN XY: 686654

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 31694

American (AMR) AF: 0.00 AC: 0 AN: 35668

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24872

East Asian (EAS) AF: 0.00 AC: 0 AN: 35928

South Asian (SAS) AF: 0.00 AC: 0 AN: 79216

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 44316

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4086

European-Non Finnish (NFE) AF: 9.27e-7 AC: 1 AN: 1078276

Other (OTH) AF: 0.00 AC: 0 AN: 57666

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

Alfa AF: 0.000111 Hom.: 0

ExAC AF: 0.0000110 AC: 1

ClinVar

ClinVar submissions

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	Benign	0.14
BayesDel_addAF	Benign	-0.070	T
BayesDel_noAF	Benign	-0.34
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.17	T
Eigen	Benign	-0.12
Eigen_PC	Benign	0.078
FATHMM_MKL	Benign	0.57	D
LIST_S2	Benign	0.84	T
M_CAP	Pathogenic	0.55	D
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	0.69	N
PhyloP100		3.9
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-0.070	N
REVEL	Benign	0.094
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.21	T
Polyphen		0.0	B
Vest4		0.18
MutPred		0.22		Loss of sheet (P = 0.0228)
MVP		0.24
MPC		1.1
ClinPred		0.63	D
GERP RS		5.3
PromoterAI		-0.12	Neutral
Varity_R		0.48
gMVP		0.65
Mutation Taster		=78/22	polymorphism

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: rs757097388; hg19: chr10-104263917;