Genetic Variant SNRNP35:p.Leu175Phe (chr12-123466063-C-T) – ACMG Classification: Benign (-8 pts)

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

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]

SNRNP35 links:

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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
SNRNP35	NM_022717.4 link	c.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	UniProt
SNRNP35	ENST00000526639.3 link	c.523C>T	p.Leu175Phe	missense_variant	Exon 2 of 2	1	NM_022717.4	ENSP00000432595.2	Q16560-1
SNRNP35	ENST00000412157.2 link	c.538C>T	p.Leu180Phe	missense_variant	Exon 2 of 2	1		ENSP00000403310.2	Q16560-2
SNRNP35	ENST00000527158.2 link	n.99-5029C>T		intron_variant	Intron 1 of 1	1
SNRNP35	ENST00000350887.5 link	c.523C>T	p.Leu175Phe	missense_variant	Exon 2 of 2	5		ENSP00000340774.5	Q16560-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000399

AC:

AN:

250552

Hom.:

AF XY:

0.00000736

AC XY:

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:

AN:

1461838

Hom.:

Cov.:

AF XY:

0.00000825

AC XY:

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.:

Alfa

AF:

0.0000468

Hom.:

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

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

LIST_S2

Benign

0.59

.;T;T

M_CAP

Benign

0.0051

MetaRNN

Benign

0.022

T;T;T

MetaSVM

Benign

-0.96

MutationAssessor

Benign

-0.28

N;.;N

PrimateAI

Benign

0.28

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

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over