chr12-123466063-C-T

Variant summary

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

The NM_022717.4(SNRNP35):​c.523C>T​(p.Leu175Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000041 in 1,461,838 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 (★).

Frequency

Genomes: not found (cov: 31)
Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

SNRNP35
NM_022717.4 missense

Scores

19

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.658
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.021856278).
BS2
High AC in GnomAdExome4 at 6 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SNRNP35NM_022717.4 linkc.523C>T p.Leu175Phe 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.523C>T p.Leu175Phe missense_variant Exon 2 of 2 1 NM_022717.4 ENSP00000432595.2 Q16560-1
SNRNP35ENST00000412157.2 linkc.538C>T p.Leu180Phe missense_variant Exon 2 of 2 1 ENSP00000403310.2 Q16560-2
SNRNP35ENST00000527158.2 linkn.99-5029C>T intron_variant Intron 1 of 1 1
SNRNP35ENST00000350887.5 linkc.523C>T p.Leu175Phe missense_variant Exon 2 of 2 5 ENSP00000340774.5 Q16560-1

Frequencies

GnomAD3 genomes
Cov.:
31
GnomAD3 exomes
AF:
0.00000399
AC:
1
AN:
250552
Hom.:
0
AF XY:
0.00000736
AC XY:
1
AN XY:
135796
show subpopulations
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 SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000882
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000410
AC:
6
AN:
1461838
Hom.:
0
Cov.:
31
AF XY:
0.00000825
AC XY:
6
AN XY:
727230
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000360
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
Cov.:
31
Alfa
AF:
0.0000468
Hom.:
0

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Dec 11, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.538C>T (p.L180F) 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 538, causing the leucine (L) at amino acid position 180 to be replaced by a phenylalanine (F). 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
0.072
BayesDel_addAF
Benign
-0.33
T
BayesDel_noAF
Benign
-0.71
CADD
Benign
7.6
DANN
Benign
0.37
DEOGEN2
Benign
0.0098
T;.;T
Eigen
Benign
-0.95
Eigen_PC
Benign
-0.79
FATHMM_MKL
Benign
0.057
N
LIST_S2
Benign
0.59
.;T;T
M_CAP
Benign
0.0051
T
MetaRNN
Benign
0.022
T;T;T
MetaSVM
Benign
-0.96
T
MutationAssessor
Benign
-0.28
N;.;N
PrimateAI
Benign
0.28
T
PROVEAN
Benign
-0.080
N;N;N
REVEL
Benign
0.070
Sift
Benign
0.87
T;T;T
Sift4G
Benign
1.0
T;T;T
Polyphen
0.0010
B;B;B
Vest4
0.095
MVP
0.072
MPC
0.39
ClinPred
0.032
T
GERP RS
3.6
Varity_R
0.024
gMVP
0.13

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: rs1309925199; hg19: chr12-123950610; API