11-65525924-G-T

Variant names:

• chr11-65525924-G-T
• rs1554967761
• NM_020680.4:c.256G>T

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_001425206.1(SCYL1):​c.-173-1G>T variant causes a splice acceptor, intron 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. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 31)
• Consequence: SCYL1 NM_001425206.1 splice_acceptor, intron
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 8.17
• Publications: 1 publications found

Genes affected

SCYL1 (HGNC:14372): (SCY1 like pseudokinase 1) This gene encodes a transcriptional regulator belonging to the SCY1-like family of kinase-like proteins. The protein has a divergent N-terminal kinase domain that is thought to be catalytically inactive, and can bind specific DNA sequences through its C-terminal domain. It activates transcription of the telomerase reverse transcriptase and DNA polymerase beta genes. The protein has been localized to the nucleus, and also to the cytoplasm and centrosomes during mitosis. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

SCYL1 Gene-Disease associations (from GenCC):

• acute infantile liver failure-cerebellar ataxia-peripheral sensory motor neuropathy syndrome

  Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: G2P, Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 10, offset of -4, new splice context is: ccctgtgtccccttccccAGaca. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-65525924-G-T is Pathogenic according to our data. Variant chr11-65525924-G-T is described in ClinVar as Pathogenic. ClinVar VariationId is 446292.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001425206.1. 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
	SCYL1	NM_020680.4	MANE Select	c.256G>T	p.Glu86*	stop_gained	Exon 3 of 18	NP_065731.3
	SCYL1	NM_001425179.1		c.256G>T	p.Glu86*	stop_gained	Exon 3 of 18	NP_001412108.1
	SCYL1	NM_001425180.1		c.256G>T	p.Glu86*	stop_gained	Exon 3 of 18	NP_001412109.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCYL1	ENST00000270176.10	TSL:1 MANE Select	c.256G>T	p.Glu86*	stop_gained	Exon 3 of 18	ENSP00000270176.5
	SCYL1	ENST00000420247.6	TSL:1	c.256G>T	p.Glu86*	stop_gained	Exon 3 of 18	ENSP00000408192.2
	SCYL1	ENST00000524944.5	TSL:1	c.256G>T	p.Glu86*	stop_gained	Exon 3 of 17	ENSP00000432175.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Acute infantile liver failure-cerebellar ataxia-peripheral sensory motor neuropathy syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	41
DANN	Uncertain	1.0
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Uncertain	0.94	D
PhyloP100		8.2
Vest4		0.89
GERP RS		4.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.19		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: rs1554967761; hg19: chr11-65293395;