Genetic Variant SNRNP35:p.Pro216Leu (chr12-123466187-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.647C>T(p.Pro216Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000368 in 1,600,808 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: 𝑓 0.00026 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00038 ( 0 hom. )

Consequence

SNRNP35
NM_022717.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.0480

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=0.015787601).

BS2

High AC in GnomAd4 at 39 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SNRNP35	NM_022717.4 link	c.647C>T	p.Pro216Leu	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.647C>T	p.Pro216Leu	missense_variant	Exon 2 of 2	1	NM_022717.4	ENSP00000432595.2	Q16560-1
SNRNP35	ENST00000412157.2 link	c.662C>T	p.Pro221Leu	missense_variant	Exon 2 of 2	1		ENSP00000403310.2	Q16560-2
SNRNP35	ENST00000527158.2 link	n.99-4905C>T		intron_variant	Intron 1 of 1	1
SNRNP35	ENST00000350887.5 link	c.647C>T	p.Pro216Leu	missense_variant	Exon 2 of 2	5		ENSP00000340774.5	Q16560-1

Frequencies

GnomAD3 genomes

AF:

0.000250

AC:

AN:

151808

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000968

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000460

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:

0.000368

Gnomad OTH

AF:

0.000961

GnomAD3 exomes

AF:

0.000257

AC:

AN:

237754

Hom.:

AF XY:

0.000265

AC XY:

AN XY:

128544

show subpopulations

Gnomad AFR exome

AF:

0.0000625

Gnomad AMR exome

AF:

0.000472

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000479

Gnomad NFE exome

AF:

0.000377

Gnomad OTH exome

AF:

0.000528

GnomAD4 exome

AF:

0.000380

AC:

550

AN:

1448882

Hom.:

Cov.:

AF XY:

0.000376

AC XY:

271

AN XY:

720278

show subpopulations

Gnomad4 AFR exome

AF:

0.000245

Gnomad4 AMR exome

AF:

0.000501

Gnomad4 ASJ exome

AF:

0.0000789

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000377

Gnomad4 NFE exome

AF:

0.000452

Gnomad4 OTH exome

AF:

0.000251

GnomAD4 genome

AF:

0.000257

AC:

AN:

151926

Hom.:

Cov.:

AF XY:

0.000202

AC XY:

AN XY:

74220

show subpopulations

Gnomad4 AFR

AF:

0.000121

Gnomad4 AMR

AF:

0.000459

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000368

Gnomad4 OTH

AF:

0.000951

Alfa

AF:

0.000404

Hom.:

Bravo

AF:

0.000280

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00156

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000198

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Nov 14, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.662C>T (p.P221L) 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 662, causing the proline (P) at amino acid position 221 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

0.083

BayesDel_addAF

Benign

-0.61

BayesDel_noAF

Benign

-0.68

CADD

Benign

3.8

DANN

Benign

0.67

DEOGEN2

Benign

0.042

T;.;T

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.14

LIST_S2

Benign

0.55

.;T;T

M_CAP

Benign

0.0088

MetaRNN

Benign

0.016

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.1

L;.;L

PrimateAI

Benign

0.37

PROVEAN

Benign

-1.2

N;N;N

REVEL

Benign

0.017

Sift

Benign

0.34

T;T;T

Sift4G

Benign

0.30

T;T;T

Polyphen

0.043

B;B;B

Vest4

0.086

MVP

0.29

MPC

0.36

ClinPred

0.0094

GERP RS

1.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.024

gMVP

0.15

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