11-65526041-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_020680.4(SCYL1):c.373G>A(p.Val125Met) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000963 in 1,612,910 control chromosomes in the GnomAD database, including 19 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0053 (8 hom., cov: 31)
  • Exomes 𝑓: 0.00051 (11 hom.)
• Consequence: SCYL1 NM_020680.4 missense, splice_region
• Scores: Splicing: ADA: 0.1835
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 6.31

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.011386067).
• BP6: Variant 11-65526041-G-A is Benign according to our data. Variant chr11-65526041-G-A is described in ClinVar as [Benign]. Clinvar id is 727353.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00527 (802/152300) while in subpopulation AFR AF= 0.0178 (738/41556). AF 95% confidence interval is 0.0167. There are 8 homozygotes in gnomad4. There are 360 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCYL1	NM_020680.4	c.373G>A	p.Val125Met	missense_variant, splice_region_variant	3/18	ENST00000270176.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCYL1	ENST00000270176.10	c.373G>A	p.Val125Met	missense_variant, splice_region_variant	3/18	1	NM_020680.4	P1

Frequencies

GnomAD3 genomes AF: 0.00526 AC: 800 AN: 152182 Hom.: 8 Cov.: 31

Gnomad AFR AF: 0.0177

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00366

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00335

GnomAD3 exomes AF: 0.00132 AC: 328 AN: 248102 Hom.: 7 AF XY: 0.00101 AC XY: 136 AN XY: 134942

Gnomad AFR exome AF: 0.0173

Gnomad AMR exome AF: 0.00139

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000557

Gnomad SAS exome AF: 0.0000981

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000267

Gnomad OTH exome AF: 0.00133

GnomAD4 exome AF: 0.000515 AC: 752 AN: 1460610 Hom.: 11 Cov.: 33 AF XY: 0.000436 AC XY: 317 AN XY: 726614

Gnomad4 AFR exome AF: 0.0167

Gnomad4 AMR exome AF: 0.00161

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000812

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000126

Gnomad4 OTH exome AF: 0.00156

GnomAD4 genome AF: 0.00527 AC: 802 AN: 152300 Hom.: 8 Cov.: 31 AF XY: 0.00483 AC XY: 360 AN XY: 74468

Gnomad4 AFR AF: 0.0178

Gnomad4 AMR AF: 0.00366

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00110 Hom.: 2

Bravo AF: 0.00614

ESP6500AA AF: 0.0153 AC: 61

ESP6500EA AF: 0.000120 AC: 1

ExAC AF: 0.00149 AC: 180

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 12, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.44
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.20
Cadd	Pathogenic	28
Dann	Uncertain	0.99
DEOGEN2	Benign	0.10	T;T;.;.;T
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.92	D;D;D;D;D
MetaRNN	Benign	0.011	T;T;T;T;T
MetaSVM	Benign	-0.47	T
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-1.2	N;N;N;N;N
REVEL	Uncertain	0.31
Sift	Benign	0.13	T;T;T;T;T
Sift4G	Uncertain	0.059	T;T;T;T;D
Polyphen		0.95	P;.;P;P;P
Vest4		0.74
MVP		0.73
MPC		0.79
ClinPred		0.041	T
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.33
gMVP		0.64

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.18
dbscSNV1_RF	Benign	0.47
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: rs78243061; hg19: chr11-65293512; COSMIC: COSV104539930; COSMIC: COSV104539930;