10-102504154-T-A

Variant names:

• chr10-102504154-T-A
• NM_016169.4:c.2T>A

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_016169.4(SUFU):​c.2T>A​(p.Met1?) variant causes a start lost change. 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 Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: SUFU NM_016169.4 start_lost
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 4.22

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 Pathogenic. Variant got 12 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 11 pathogenic variants. Next in-frame start position is after 73 codons. Genomic position: 102509203. Lost 0.149 part of the original CDS.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 10-102504154-T-A is Pathogenic according to our data. Variant chr10-102504154-T-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2566871.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SUFU	NM_016169.4	c.2T>A	p.Met1?	start_lost	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.2T>A	p.Met1?	start_lost	Exon 1 of 12	1	NM_016169.4	ENSP00000358918.4
SUFU	ENST00000423559.2	c.2T>A	p.Met1?	start_lost	Exon 1 of 10	1		ENSP00000411597.2
SUFU	ENST00000369899.6	c.2T>A	p.Met1?	start_lost	Exon 1 of 11	1		ENSP00000358915.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary cancer-predisposing syndrome Pathogenic:1

Dec 16, 2024

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.M1? variant (also known as c.2T>A) is located in coding exon 1 of the SUFU gene and results from a T to A substitution at nucleotide position 2. This alters the methionine residue at the initiation codon (ATG). This amino acid position is well conserved in available vertebrate species. Sequence variations that modify the initiation codon are expected to result in either loss of translation initiation, N-terminal truncation, or cause a shift in the mRNA reading frame. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.23
CADD	Benign	23
DANN	Benign	0.97
DEOGEN2	Benign	0.17	T;.;.
Eigen	Benign	-0.16
Eigen_PC	Benign	-0.031
FATHMM_MKL	Benign	0.67	D
LIST_S2	Uncertain	0.90	D;D;D
M_CAP	Pathogenic	0.97	D
MetaRNN	Pathogenic	0.98	D;D;D
MetaSVM	Benign	-0.84	T
PROVEAN	Benign	-0.17	N;N;N
REVEL	Uncertain	0.34
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		0.0020	B;B;B
Vest4		0.78
MutPred		0.85		Gain of ubiquitination at M1 (P = 0.0114);Gain of ubiquitination at M1 (P = 0.0114);Gain of ubiquitination at M1 (P = 0.0114);
MVP		0.86
ClinPred		1.0	D
GERP RS		4.1
Varity_R		0.99
gMVP		0.86

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr10-104263911;