rs200061483

Variant names:

• chr10-102504318-G-A
• rs200061483
• NM_016169.4:c.166G>A

Your query was ambiguous. Multiple possible variants found:

• chr10-102504318-G-A
• chr10-102504318-G-T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_016169.4(SUFU):​c.166G>A​(p.Ala56Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A56S) 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: 9.13
• 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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.803

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SUFU	NM_016169.4	c.166G>A	p.Ala56Thr	missense_variant	Exon 1 of 12	ENST00000369902.8	NP_057253.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SUFU	ENST00000369902.8	c.166G>A	p.Ala56Thr	missense_variant	Exon 1 of 12	1	NM_016169.4	ENSP00000358918.4
SUFU	ENST00000423559.2	c.166G>A	p.Ala56Thr	missense_variant	Exon 1 of 10	1		ENSP00000411597.2
SUFU	ENST00000369899.6	c.166G>A	p.Ala56Thr	missense_variant	Exon 1 of 11	1		ENSP00000358915.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 52

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.040
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Benign	0.19	T;.;.
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.95	D;D;D
M_CAP	Uncertain	0.14	D
MetaRNN	Pathogenic	0.80	D;D;D
MetaSVM	Benign	-0.35	T
MutationAssessor	Benign	0.90	L;L;L
PhyloP100		9.1
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-0.77	N;N;N
REVEL	Uncertain	0.59
Sift	Benign	0.44	T;T;T
Sift4G	Benign	0.47	T;T;T
Polyphen		1.0	D;D;D
Vest4		0.78
MutPred		0.49		Gain of sheet (P = 0.0266);Gain of sheet (P = 0.0266);Gain of sheet (P = 0.0266);
MVP		0.58
MPC		0.64
ClinPred		0.92	D
GERP RS		4.7
PromoterAI		0.031	Neutral
Varity_R		0.55
gMVP		0.59
Mutation Taster		=38/62	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		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: rs200061483; hg19: chr10-104264075;