1-169855868-A-G

Position:

• chr1-169855868-A-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_181093.4(SCYL3):​c.1402T>C​(p.Phe468Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SCYL3 NM_181093.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0140

Genes affected

SCYL3 (HGNC:19285): (SCY1 like pseudokinase 3) This gene encodes a protein with a kinase domain and four HEAT repeats. The encoded protein interacts with the C-terminal domain of ezrin, an ERM protein, and may play a role in cell adhesion and migration. Alternative splicing results in multiple transcript variants encoding multiple isoforms. [provided by RefSeq, Jun 2012]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.045862526).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCYL3	NM_020423.7	c.1313-904T>C		intron_variant		ENST00000367771.11	NP_065156.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCYL3	ENST00000367770.5	c.1402T>C	p.Phe468Leu	missense_variant	11/13	1		ENSP00000356744.1
SCYL3	ENST00000367771.11	c.1313-904T>C		intron_variant		1	NM_020423.7	ENSP00000356745.5
SCYL3	ENST00000367772.8	c.1402T>C	p.Phe468Leu	missense_variant	12/14	2		ENSP00000356746.4
SCYL3	ENST00000423670.1	c.1313-904T>C		intron_variant		5		ENSP00000407993.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 12, 2024

The c.1402T>C (p.F468L) alteration is located in exon 12 (coding exon 11) of the SCYL3 gene. This alteration results from a T to C substitution at nucleotide position 1402, causing the phenylalanine (F) at amino acid position 468 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	13
DANN	Benign	0.78
DEOGEN2	Benign	0.0037	T;T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.036	N
LIST_S2	Benign	0.39	.;T
M_CAP	Benign	0.0024	T
MetaRNN	Benign	0.046	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	L;L
PrimateAI	Benign	0.36	T
PROVEAN	Benign	1.0	N;N
REVEL	Benign	0.065
Sift	Benign	1.0	T;T
Sift4G	Benign	0.76	T;T
Polyphen		0.0	B;B
Vest4		0.16
MutPred		0.32		Gain of loop (P = 0.0097);Gain of loop (P = 0.0097);
MVP		0.51
MPC		0.23
ClinPred		0.041	T
GERP RS		2.0
Varity_R		0.13
gMVP		0.18

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: rs1659094032; hg19: chr1-169825009;