rs587778697

Variant names:

• chr10-102592645-G-A
• rs587778697
• NM_016169.4:c.518G>A

Your query was ambiguous. Multiple possible variants found:

• chr10-102592645-G-A
• chr10-102592645-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.518G>A​(p.Arg173Lys) 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. Variant has been reported in ClinVar as not provided (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R173I) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SUFU NM_016169.4 missense
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: 9.60
• Publications: 2 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, 0.756

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SUFU	NM_016169.4	c.518G>A	p.Arg173Lys	missense_variant	Exon 4 of 12	ENST00000369902.8	NP_057253.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SUFU	ENST00000369902.8	c.518G>A	p.Arg173Lys	missense_variant	Exon 4 of 12	1	NM_016169.4	ENSP00000358918.4
SUFU	ENST00000423559.2	c.518G>A	p.Arg173Lys	missense_variant	Exon 4 of 10	1		ENSP00000411597.2
SUFU	ENST00000369899.6	c.518G>A	p.Arg173Lys	missense_variant	Exon 4 of 11	1		ENSP00000358915.2
SUFU	ENST00000471000.1	n.300G>A		non_coding_transcript_exon_variant	Exon 2 of 6	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: not provided

Submissions summary: Other:1

Revision: no classification provided

Submissions by phenotype

not specified Other:1

Sep 19, 2013

ITMI

Significance: not provided

Review Status: no classification provided

Collection Method: reference population

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.58
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.19
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Benign	0.34	T;.;.
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	D;D;D
M_CAP	Benign	0.040	D
MetaRNN	Pathogenic	0.76	D;D;D
MetaSVM	Uncertain	-0.24	T
MutationAssessor	Benign	1.7	L;L;L
PhyloP100		9.6
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	-1.9	N;N;N
REVEL	Pathogenic	0.70
Sift	Benign	0.14	T;T;T
Sift4G	Benign	0.14	T;T;T
Polyphen		0.99	D;D;P
Vest4		0.75
MutPred		0.50		Gain of ubiquitination at R173 (P = 0.0075);Gain of ubiquitination at R173 (P = 0.0075);Gain of ubiquitination at R173 (P = 0.0075);
MVP		0.86
MPC		1.5
ClinPred		0.93	D
GERP RS		5.3
Varity_R		0.57
gMVP		0.72
Mutation Taster		=54/46	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs587778697; hg19: chr10-104352402; COSMIC: COSV105285744;