rs761240106

Variant names:

• chr10-102504217-C-A
• rs761240106
• NM_016169.4:c.65C>A

Your query was ambiguous. Multiple possible variants found:

• chr10-102504217-C-A
• chr10-102504217-C-G
• chr10-102504217-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_016169.4(SUFU):​c.65C>A​(p.Ala22Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 1,453,472 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. A22G) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: SUFU NM_016169.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 2.39
• Publications: 1 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.32328853).

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.65C>A	p.Ala22Asp	missense	Exon 1 of 12	NP_057253.2
	SUFU	NM_001178133.2		c.65C>A	p.Ala22Asp	missense	Exon 1 of 11	NP_001171604.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SUFU	ENST00000369902.8	TSL:1 MANE Select	c.65C>A	p.Ala22Asp	missense	Exon 1 of 12	ENSP00000358918.4
	SUFU	ENST00000423559.2	TSL:1	c.65C>A	p.Ala22Asp	missense	Exon 1 of 10	ENSP00000411597.2
	SUFU	ENST00000369899.6	TSL:1	c.65C>A	p.Ala22Asp	missense	Exon 1 of 11	ENSP00000358915.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1453472 Hom.: 0 Cov.: 52 AF XY: 0.00000277 AC XY: 2 AN XY: 722796

African (AFR) AF: 0.00 AC: 0 AN: 33248

American (AMR) AF: 0.00 AC: 0 AN: 44262

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25986

East Asian (EAS) AF: 0.00 AC: 0 AN: 39348

South Asian (SAS) AF: 0.00 AC: 0 AN: 85582

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51584

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5496

European-Non Finnish (NFE) AF: 0.00000181 AC: 2 AN: 1108032

Other (OTH) AF: 0.0000167 AC: 1 AN: 59934

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	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	0.30
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Benign	-0.090
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.13	T
Eigen	Benign	0.14
Eigen_PC	Benign	0.17
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.84	T
M_CAP	Pathogenic	0.33	D
MetaRNN	Benign	0.32	T
MetaSVM	Benign	-0.76	T
MutationAssessor	Benign	0.69	N
PhyloP100		2.4
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	0.070	N
REVEL	Benign	0.26
Sift	Benign	0.083	T
Sift4G	Benign	0.59	T
Polyphen		0.91	P
Vest4		0.27
MutPred		0.10		Loss of glycosylation at P24 (P = 0.0975)
MVP		0.36
MPC		1.6
ClinPred		0.84	D
GERP RS		4.9
PromoterAI		-0.046	Neutral
Varity_R		0.44
gMVP		0.60
Mutation Taster		=62/38	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: rs761240106; hg19: chr10-104263974;