rs8181357

Positions:

• chr10-133557135-C-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001143764.3(SYCE1):​c.396G>T​(p.Glu132Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.108 in 1,611,392 control chromosomes in the GnomAD database, including 11,017 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.098 (882 hom., cov: 33)
  • Exomes 𝑓: 0.11 (10135 hom.)
• Consequence: SYCE1 NM_001143764.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.669

Genes affected

SYCE1 (HGNC:28852): (synaptonemal complex central element protein 1) This gene encodes a member of the synaptonemal complex, which links homologous chromosomes during prophase I of meiosis. The tripartite structure of the complex is highly conserved amongst metazoans. It consists of two lateral elements and a central region formed by transverse elements and a central element. The protein encoded by this gene localizes to the central element and is required for initiation and elongation of the synapsis. Allelic variants of this gene have been associated with premature ovarian failure and spermatogenic failure. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Nov 2016]

CYP2E1 (HGNC:2631): (cytochrome P450 family 2 subfamily E member 1) This gene encodes a member of the cytochrome P450 superfamily of enzymes. The cytochrome P450 proteins are monooxygenases which catalyze many reactions involved in drug metabolism and synthesis of cholesterol, steroids and other lipids. This protein localizes to the endoplasmic reticulum and is induced by ethanol, the diabetic state, and starvation. The enzyme metabolizes both endogenous substrates, such as ethanol, acetone, and acetal, as well as exogenous substrates including benzene, carbon tetrachloride, ethylene glycol, and nitrosamines which are premutagens found in cigarette smoke. Due to its many substrates, this enzyme may be involved in such varied processes as gluconeogenesis, hepatic cirrhosis, diabetes, and cancer. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.002853632).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.241 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SYCE1	NM_001143764.3	c.396G>T	p.Glu132Asp	missense_variant	7/13	ENST00000343131.7	NP_001137236.1
SYCE1	NM_001143763.2	c.396G>T	p.Glu132Asp	missense_variant	7/13		NP_001137235.1
SYCE1	NM_130784.4	c.288G>T	p.Glu96Asp	missense_variant	7/13		NP_570140.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SYCE1	ENST00000343131.7	c.396G>T	p.Glu132Asp	missense_variant	7/13	1	NM_001143764.3	ENSP00000341282	A2

Frequencies

GnomAD3 genomes AF: 0.0978 AC: 14860 AN: 152014 Hom.: 879 Cov.: 33

Gnomad AFR AF: 0.0577

Gnomad AMI AF: 0.0846

Gnomad AMR AF: 0.124

Gnomad ASJ AF: 0.101

Gnomad EAS AF: 0.253

Gnomad SAS AF: 0.194

Gnomad FIN AF: 0.120

Gnomad MID AF: 0.0570

Gnomad NFE AF: 0.0942

Gnomad OTH AF: 0.0995

GnomAD3 exomes AF: 0.126 AC: 31638 AN: 251084 Hom.: 2398 AF XY: 0.127 AC XY: 17222 AN XY: 135712

Gnomad AFR exome AF: 0.0566

Gnomad AMR exome AF: 0.155

Gnomad ASJ exome AF: 0.0970

Gnomad EAS exome AF: 0.254

Gnomad SAS exome AF: 0.189

Gnomad FIN exome AF: 0.124

Gnomad NFE exome AF: 0.0932

Gnomad OTH exome AF: 0.114

GnomAD4 exome AF: 0.109 AC: 159706 AN: 1459260 Hom.: 10135 Cov.: 31 AF XY: 0.111 AC XY: 80583 AN XY: 726018

Gnomad4 AFR exome AF: 0.0556

Gnomad4 AMR exome AF: 0.153

Gnomad4 ASJ exome AF: 0.0993

Gnomad4 EAS exome AF: 0.267

Gnomad4 SAS exome AF: 0.188

Gnomad4 FIN exome AF: 0.121

Gnomad4 NFE exome AF: 0.0973

Gnomad4 OTH exome AF: 0.112

GnomAD4 genome AF: 0.0977 AC: 14867 AN: 152132 Hom.: 882 Cov.: 33 AF XY: 0.103 AC XY: 7636 AN XY: 74384

Gnomad4 AFR AF: 0.0576

Gnomad4 AMR AF: 0.125

Gnomad4 ASJ AF: 0.101

Gnomad4 EAS AF: 0.253

Gnomad4 SAS AF: 0.193

Gnomad4 FIN AF: 0.120

Gnomad4 NFE AF: 0.0942

Gnomad4 OTH AF: 0.0980

Alfa AF: 0.0996 Hom.: 1647

Bravo AF: 0.0960

TwinsUK AF: 0.109 AC: 404

ALSPAC AF: 0.0963 AC: 371

ESP6500AA AF: 0.0622 AC: 274

ESP6500EA AF: 0.0956 AC: 822

ExAC AF: 0.123 AC: 14899

EpiCase AF: 0.0956

EpiControl AF: 0.0935

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.77	T
BayesDel_noAF	Benign	-0.74
CADD	Benign	12
DANN	Uncertain	0.99
DEOGEN2	Benign	0.027	.;T;T
Eigen	Benign	-0.62
Eigen_PC	Benign	-0.59
FATHMM_MKL	Benign	0.061	N
LIST_S2	Benign	0.55	T;T;T
MetaRNN	Benign	0.0029	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.9	.;.;L
MutationTaster	Benign	0.99	P;P;P;P;P
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-1.1	N;N;N
REVEL	Benign	0.061
Sift	Benign	0.14	T;T;T
Sift4G	Benign	0.080	T;T;T
Polyphen		0.015	B;.;B
Vest4		0.12
MutPred		0.072		.;Loss of ubiquitination at K134 (P = 0.1191);Loss of ubiquitination at K134 (P = 0.1191);
MPC		0.18
ClinPred		0.0071	T
GERP RS		0.22
Varity_R		0.11
gMVP		0.028

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs8181357; hg19: chr10-135370639; COSMIC: COSV58216350;