12-123466127-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_022717.4(SNRNP35):​c.587C>T​(p.Ser196Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000869 in 1,611,712 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S196W) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 31)
Exomes 𝑓: 0.0000082 ( 0 hom. )

Consequence

SNRNP35
NM_022717.4 missense

Scores

1
18

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.29
Variant links:
Genes affected
SNRNP35 (HGNC:30852): (small nuclear ribonucleoprotein U11/U12 subunit 35) The protein encoded by this gene is a homolog of the U1-snRNP binding protein. The N-terminal half contains a RNA recognition motif and the C-terminal half is rich in Arg/Asp and Arg/Glu dipeptides, which is a characteristic of a variety of splicing factors. This protein is a component of the U11/U12 small nuclear ribonucleoproteins (snRNP) that form part of the U12-type spliceosome. Alternative splicing results in multiple transcript variants encoding two distinct isoforms and representing a non-protein coding variant. [provided by RefSeq, Aug 2013]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.043331355).
BS2
High AC in GnomAdExome4 at 12 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SNRNP35NM_022717.4 linkc.587C>T p.Ser196Leu missense_variant Exon 2 of 2 ENST00000526639.3 NP_073208.1 Q16560-1A0A024RBU2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SNRNP35ENST00000526639.3 linkc.587C>T p.Ser196Leu missense_variant Exon 2 of 2 1 NM_022717.4 ENSP00000432595.2 Q16560-1
SNRNP35ENST00000412157.2 linkc.602C>T p.Ser201Leu missense_variant Exon 2 of 2 1 ENSP00000403310.2 Q16560-2
SNRNP35ENST00000527158.2 linkn.99-4965C>T intron_variant Intron 1 of 1 1
SNRNP35ENST00000350887.5 linkc.587C>T p.Ser196Leu missense_variant Exon 2 of 2 5 ENSP00000340774.5 Q16560-1

Frequencies

GnomAD3 genomes
AF:
0.0000132
AC:
2
AN:
151838
Hom.:
0
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.0000484
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000401
AC:
10
AN:
249574
Hom.:
0
AF XY:
0.0000222
AC XY:
3
AN XY:
135024
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000235
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000177
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000822
AC:
12
AN:
1459874
Hom.:
0
Cov.:
31
AF XY:
0.00000689
AC XY:
5
AN XY:
726164
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.000203
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000180
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000132
AC:
2
AN:
151838
Hom.:
0
Cov.:
31
AF XY:
0.00
AC XY:
0
AN XY:
74118
show subpopulations
Gnomad4 AFR
AF:
0.0000484
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000116
AC:
1
ExAC
AF:
0.0000577
AC:
7
EpiCase
AF:
0.0000545
EpiControl
AF:
0.0000593

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Dec 15, 2023
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.602C>T (p.S201L) alteration is located in exon 2 (coding exon 2) of the SNRNP35 gene. This alteration results from a C to T substitution at nucleotide position 602, causing the serine (S) at amino acid position 201 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
0.11
BayesDel_addAF
Benign
-0.36
T
BayesDel_noAF
Benign
-0.53
CADD
Benign
18
DANN
Benign
0.88
DEOGEN2
Benign
0.040
T;.;T
Eigen
Benign
-0.60
Eigen_PC
Benign
-0.50
FATHMM_MKL
Uncertain
0.84
D
LIST_S2
Benign
0.78
.;T;T
M_CAP
Benign
0.0072
T
MetaRNN
Benign
0.043
T;T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
0.69
N;.;N
PrimateAI
Benign
0.43
T
PROVEAN
Benign
-1.7
N;N;N
REVEL
Benign
0.025
Sift
Benign
0.14
T;T;T
Sift4G
Benign
0.71
T;T;T
Polyphen
0.063
B;B;B
Vest4
0.16
MVP
0.57
MPC
0.33
ClinPred
0.12
T
GERP RS
1.3
Varity_R
0.048
gMVP
0.14

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs146087320; hg19: chr12-123950674; COSMIC: COSV100644612; COSMIC: COSV100644612; API