NM_020680.4:c.1412C>T

Variant names:

• chr11-65535978-C-T
• rs1554969894
• NM_020680.4:c.1412C>T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Moderate PP5_Moderate

The NM_020680.4(SCYL1):​c.1412C>T​(p.Ala471Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000275 in 1,456,492 control chromosomes in the GnomAD database, with no homozygous occurrence. 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)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: SCYL1 NM_020680.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 4.26
• Publications: 0 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, Labcorp Genetics (formerly Invitae), Ambry Genetics, PanelApp Australia, Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.851
• PP5: Variant 11-65535978-C-T is Pathogenic according to our data. Variant chr11-65535978-C-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 548462.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020680.4. 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.1412C>T	p.Ala471Val	missense	Exon 11 of 18	NP_065731.3
	SCYL1	NM_001425179.1		c.1412C>T	p.Ala471Val	missense	Exon 11 of 18	NP_001412108.1
	SCYL1	NM_001425180.1		c.1409C>T	p.Ala470Val	missense	Exon 11 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.1412C>T	p.Ala471Val	missense	Exon 11 of 18	ENSP00000270176.5	Q96KG9-1
	SCYL1	ENST00000420247.6	TSL:1	c.1412C>T	p.Ala471Val	missense	Exon 11 of 18	ENSP00000408192.2	Q96KG9-2
	SCYL1	ENST00000524944.5	TSL:1	c.1412C>T	p.Ala471Val	missense	Exon 11 of 17	ENSP00000432175.1	E9PS17

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000275 AC: 4 AN: 1456492 Hom.: 0 Cov.: 32 AF XY: 0.00000276 AC XY: 2 AN XY: 724434

African (AFR) AF: 0.00 AC: 0 AN: 33314

American (AMR) AF: 0.00 AC: 0 AN: 43948

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25716

East Asian (EAS) AF: 0.00 AC: 0 AN: 39668

South Asian (SAS) AF: 0.00 AC: 0 AN: 85544

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53258

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5742

European-Non Finnish (NFE) AF: 0.00000361 AC: 4 AN: 1109124

Other (OTH) AF: 0.00 AC: 0 AN: 60178

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

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
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.070
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.54	D
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.026	D
MetaRNN	Pathogenic	0.85	D
MetaSVM	Benign	-0.49	T
PhyloP100		4.3
PrimateAI	Pathogenic	0.79	T
PROVEAN	Uncertain	-3.5	D
REVEL	Uncertain	0.37
Sift	Uncertain	0.014	D
Sift4G	Uncertain	0.0050	D
Polyphen		1.0	D
Vest4		0.83
MutPred		0.76		Loss of helix (P = 0.028)
MVP		0.53
MPC		1.0
ClinPred		0.99	D
GERP RS		5.3
PromoterAI		-0.0042	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.29
gMVP		0.67
Mutation Taster		=18/82	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		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: rs1554969894; hg19: chr11-65303449; COSMIC: COSV54215259; COSMIC: COSV54215259;