Genetic Variant SYVN1:p.His358Arg (chr11-65130692-T-C) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_172230.3(SYVN1):c.1073A>G(p.His358Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 15/22 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. H358P) has been classified as Benign.

Frequency

Genomes: not found (cov: 0)

Exomes 𝑓: 0.0000029 ( 0 hom. )

Consequence

SYVN1
NM_172230.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.656

Publications

5 publications found

Variant links:

Genes affected

SYVN1 (HGNC:20738): (synoviolin 1) This gene encodes a protein involved in endoplasmic reticulum (ER)-associated degradation. The encoded protein removes unfolded proteins, accumulated during ER stress, by retrograde transport to the cytosol from the ER. This protein also uses the ubiquitin-proteasome system for additional degradation of unfolded proteins. Sequence analysis identified two transcript variants that encode different isoforms. [provided by RefSeq, May 2011]

SYVN1 Gene-Disease associations (from GenCC):

schizophrenia
Inheritance: Unknown Classification: NO_KNOWN Submitted by: Labcorp Genetics (formerly Invitae)

SYVN1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.09822282).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SYVN1	NM_172230.3 link	c.1073A>G	p.His358Arg	missense_variant	Exon 11 of 16	ENST00000377190.8	NP_757385.1	Q86TM6-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SYVN1	ENST00000377190.8 link	c.1073A>G	p.His358Arg	missense_variant	Exon 11 of 16	1	NM_172230.3	ENSP00000366395.3		Q86TM6-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00

AC:

AN:

48092

AF XY:

0.00

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000294

AC:

AN:

339728

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

173048

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

8230

American (AMR)

AF:

0.00

AC:

AN:

11096

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

5656

East Asian (EAS)

AF:

0.00

AC:

AN:

11000

South Asian (SAS)

AF:

0.00

AC:

AN:

30970

European-Finnish (FIN)

AF:

0.0000856

AC:

AN:

11682

Middle Eastern (MID)

AF:

0.00

AC:

AN:

986

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

245308

Other (OTH)

AF:

0.00

AC:

AN:

14800

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.57

CADD

Benign

(source)

DANN

Benign

0.64

DEOGEN2

Benign

0.24

.;T;.;.

Eigen

Benign

-0.44

Eigen_PC

Benign

-0.41

FATHMM_MKL

Benign

0.67

LIST_S2

Benign

0.76

.;T;T;T

M_CAP

Benign

0.013

MetaRNN

Benign

0.098

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.4

L;L;.;L

PhyloP100

0.66

PrimateAI

Uncertain

0.64

PROVEAN

Benign

-1.3

N;N;N;N

REVEL

Benign

0.073

Sift

Benign

0.69

T;T;T;T

Sift4G

Benign

0.49

T;T;T;T

Polyphen

0.32

B;B;P;B

Vest4

0.19

MutPred

0.32

Gain of glycosylation at P355 (P = 0.252);Gain of glycosylation at P355 (P = 0.252);.;Gain of glycosylation at P355 (P = 0.252);

MVP

0.47

MPC

0.034

ClinPred

0.20

GERP RS

4.7

Varity_R

0.044

gMVP

0.12

Mutation Taster

=86/14

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over