rs1554852272

Variant names:

• chr10-102592654-A-G
• rs1554852272
• NM_016169.4:c.527A>G

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP3_Moderate PP5

The NM_016169.4(SUFU):​c.527A>G​(p.His176Arg) 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 Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SUFU NM_016169.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 8.95

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.884
• PP5: Variant 10-102592654-A-G is Pathogenic according to our data. Variant chr10-102592654-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 446157.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr10-102592654-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SUFU	NM_016169.4	c.527A>G	p.His176Arg	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.527A>G	p.His176Arg	missense_variant	Exon 4 of 12	1	NM_016169.4	ENSP00000358918.4
SUFU	ENST00000423559.2	c.527A>G	p.His176Arg	missense_variant	Exon 4 of 10	1		ENSP00000411597.2
SUFU	ENST00000369899.6	c.527A>G	p.His176Arg	missense_variant	Exon 4 of 11	1		ENSP00000358915.2
SUFU	ENST00000471000.1	n.309A>G		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: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Joubert syndrome 32 Pathogenic:1

Nov 07, 2017

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.37
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.70	D;.;.
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D;D;D
M_CAP	Uncertain	0.15	D
MetaRNN	Pathogenic	0.88	D;D;D
MetaSVM	Uncertain	0.43	D
MutationAssessor	Uncertain	2.9	M;M;M
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-5.3	D;D;D
REVEL	Pathogenic	0.80
Sift	Uncertain	0.0090	D;D;D
Sift4G	Benign	0.061	T;T;T
Polyphen		1.0	D;D;D
Vest4		0.91
MutPred		0.45		Loss of catalytic residue at L178 (P = 0.038);Loss of catalytic residue at L178 (P = 0.038);Loss of catalytic residue at L178 (P = 0.038);
MVP		0.93
MPC		1.8
ClinPred		0.99	D
GERP RS		5.3
Varity_R		0.87
gMVP		0.94

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

Publications

LitVar

Other links and lift over

dbSNP: rs1554852272; hg19: chr10-104352411;