chr12-123466187-C-T

Variant names:

• chr12-123466187-C-T
• rs142113918
• NM_022717.4:c.647C>T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

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. 16/22 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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0480
• Publications: 2 publications found

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]

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.015787601).
• BS2: High AC in GnomAd4 at 39 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_022717.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SNRNP35	NM_022717.4	MANE Select	c.647C>T	p.Pro216Leu	missense	Exon 2 of 2	NP_073208.1	Q16560-1
	SNRNP35	NM_180699.3		c.662C>T	p.Pro221Leu	missense	Exon 2 of 2	NP_851030.1	Q16560-2
	SNRNP35	NR_104103.2		n.79-4905C>T		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SNRNP35	ENST00000526639.3	TSL:1 MANE Select	c.647C>T	p.Pro216Leu	missense	Exon 2 of 2	ENSP00000432595.2	Q16560-1
	SNRNP35	ENST00000412157.2	TSL:1	c.662C>T	p.Pro221Leu	missense	Exon 2 of 2	ENSP00000403310.2	Q16560-2
	SNRNP35	ENST00000527158.2	TSL:1	n.99-4905C>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.000250 AC: 38 AN: 151808 Hom.: 0 Cov.: 31

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

GnomAD2 exomes AF: 0.000257 AC: 61 AN: 237754 AF XY: 0.000265

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 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.: 0 Cov.: 31 AF XY: 0.000376 AC XY: 271 AN XY: 720278

African (AFR) AF: 0.000245 AC: 8 AN: 32710

American (AMR) AF: 0.000501 AC: 21 AN: 41942

Ashkenazi Jewish (ASJ) AF: 0.0000789 AC: 2 AN: 25338

East Asian (EAS) AF: 0.00 AC: 0 AN: 39614

South Asian (SAS) AF: 0.00 AC: 0 AN: 84206

European-Finnish (FIN) AF: 0.0000377 AC: 2 AN: 52998

Middle Eastern (MID) AF: 0.000353 AC: 2 AN: 5670

European-Non Finnish (NFE) AF: 0.000452 AC: 500 AN: 1106654

Other (OTH) AF: 0.000251 AC: 15 AN: 59750

GnomAD4 genome AF: 0.000257 AC: 39 AN: 151926 Hom.: 0 Cov.: 31 AF XY: 0.000202 AC XY: 15 AN XY: 74220

African (AFR) AF: 0.000121 AC: 5 AN: 41426

American (AMR) AF: 0.000459 AC: 7 AN: 15234

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4794

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10560

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000368 AC: 25 AN: 67964

Other (OTH) AF: 0.000951 AC: 2 AN: 2104

Alfa AF: 0.000367 Hom.: 0

Bravo AF: 0.000280

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000198 AC: 24

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	3.8
DANN	Benign	0.67
DEOGEN2	Benign	0.042	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.55	T
M_CAP	Benign	0.0088	T
MetaRNN	Benign	0.016	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	L
PhyloP100		-0.048
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.017
Sift	Benign	0.34	T
Sift4G	Benign	0.30	T
Polyphen		0.043	B
Vest4		0.086
MVP		0.29
MPC		0.36
ClinPred		0.0094	T
GERP RS		1.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.024
gMVP		0.15
Mutation Taster		=97/3	polymorphism

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

Other links and lift over

dbSNP: rs142113918; hg19: chr12-123950734;