Genetic Variant NM_001143764.3:c.528C>A (chr10-133556759-G-T) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_001143764.3(SYCE1):c.528C>A(p.His176Gln) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. H176H) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)

Consequence

SYCE1
NM_001143764.3 missense, splice_region

Scores

Splicing: ADA: 0.00002202

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.52

Publications

1 publications found

Variant links:

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]

SYCE1 links:

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]

CYP2E1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.868

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001143764.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SYCE1	NM_001143764.3	MANE Select	c.528C>A	p.His176Gln	missense splice_region	Exon 8 of 13	NP_001137236.1	Q8N0S2-1
SYCE1	NM_001143763.2		c.528C>A	p.His176Gln	missense splice_region	Exon 8 of 13	NP_001137235.1	A0A0B4J1R9
SYCE1	NM_130784.4		c.420C>A	p.His140Gln	missense splice_region	Exon 8 of 13	NP_570140.1	Q8N0S2-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SYCE1	ENST00000343131.7	TSL:1 MANE Select	c.528C>A	p.His176Gln	missense splice_region	Exon 8 of 13	ENSP00000341282.5	Q8N0S2-1
SYCE1	ENST00000303903.10	TSL:1	c.528C>A	p.His176Gln	missense splice_region	Exon 8 of 13	ENSP00000303978.5	A0A0B4J1R9
CYP2E1	ENST00000368520.1	TSL:1	n.3457G>T		non_coding_transcript_exon	Exon 6 of 6

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.63

BayesDel_addAF

Uncertain

0.14

BayesDel_noAF

Uncertain

-0.040

CADD

Benign

(source)

DANN

Benign

0.93

DEOGEN2

Benign

0.21

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.089

LIST_S2

Benign

0.62

M_CAP

Benign

0.025

MetaRNN

Pathogenic

0.87

MetaSVM

Benign

-0.63

MutationAssessor

Uncertain

2.7

PhyloP100

-1.5

PrimateAI

Uncertain

0.65

PROVEAN

Pathogenic

-5.2

REVEL

Uncertain

0.39

Sift

Uncertain

0.012

Sift4G

Benign

0.32

Polyphen

1.0

Vest4

0.83

MutPred

0.63

Gain of disorder (P = 0.07)

MVP

0.27

MPC

0.69

ClinPred

0.99

GERP RS

-9.3

Varity_R

0.42

gMVP

0.14

Mutation Taster

=91/9

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000022

dbscSNV1_RF

Benign

0.13

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over