Genetic Variant SYMPK:p.Pro1184Leu (chr19-45815987-G-A) – ACMG Classification: Benign (-8 pts)

Variant summary

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

The NM_004819.3(SYMPK):c.3551C>T(p.Pro1184Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00118 in 1,607,726 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 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. P1184S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00062 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0012 ( 3 hom. )

Consequence

SYMPK
NM_004819.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.991

Variant links:

Genes affected

SYMPK (HGNC:22935): (symplekin scaffold protein) This gene encodes a nuclear protein that functions in the regulation of polyadenylation and promotes gene expression. The protein forms a high-molecular weight complex with components of the polyadenylation machinery. It is thought to serve as a scaffold for recruiting regulatory factors to the polyadenylation complex. It also participates in 3'-end maturation of histone mRNAs, which do not undergo polyadenylation. The protein also localizes to the cytoplasmic plaques of tight junctions in some cell types. [provided by RefSeq, Jul 2008]

SYMPK links:

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=0.014912337).

BS2

High AC in GnomAd4 at 94 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SYMPK	NM_004819.3 link	c.3551C>T	p.Pro1184Leu	missense_variant	Exon 26 of 27	ENST00000245934.12	NP_004810.2	Q92797-1A0A024R0R6
SYMPK	XM_011527354.2 link	c.3551C>T	p.Pro1184Leu	missense_variant	Exon 27 of 28		XP_011525656.1	Q92797-1A0A024R0R6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SYMPK	ENST00000245934.12 link	c.3551C>T	p.Pro1184Leu	missense_variant	Exon 26 of 27	1	NM_004819.3	ENSP00000245934.7		Q92797-1

Frequencies

GnomAD3 genomes

AF:

0.000618

AC:

AN:

152206

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000193

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000942

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00119

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000511

AC:

117

AN:

228808

Hom.:

AF XY:

0.000419

AC XY:

AN XY:

126546

show subpopulations

Gnomad AFR exome

AF:

0.000154

Gnomad AMR exome

AF:

0.000180

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000339

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000347

Gnomad NFE exome

AF:

0.000918

Gnomad OTH exome

AF:

0.000706

GnomAD4 exome

AF:

0.00124

AC:

1801

AN:

1455402

Hom.:

Cov.:

AF XY:

0.00117

AC XY:

847

AN XY:

723512

show subpopulations

Gnomad4 AFR exome

AF:

0.000179

Gnomad4 AMR exome

AF:

0.000204

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000202

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000214

Gnomad4 NFE exome

AF:

0.00151

Gnomad4 OTH exome

AF:

0.00155

GnomAD4 genome

AF:

0.000617

AC:

AN:

152324

Hom.:

Cov.:

AF XY:

0.000604

AC XY:

AN XY:

74482

show subpopulations

Gnomad4 AFR

AF:

0.000192

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000942

Gnomad4 NFE

AF:

0.00119

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.00101

Hom.:

Bravo

AF:

0.000631

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00156

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000482

AC:

ExAC

AF:

0.000468

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jul 06, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3551C>T (p.P1184L) alteration is located in exon 26 (coding exon 25) of the SYMPK gene. This alteration results from a C to T substitution at nucleotide position 3551, causing the proline (P) at amino acid position 1184 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

0.074

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.49

CADD

Benign

DANN

Benign

0.94

DEOGEN2

Benign

0.060

Eigen

Benign

-0.82

Eigen_PC

Benign

-0.80

FATHMM_MKL

Benign

0.058

LIST_S2

Benign

0.52

M_CAP

Benign

0.0094

MetaRNN

Benign

0.015

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.5

PrimateAI

Benign

0.46

PROVEAN

Benign

-0.070

REVEL

Benign

0.026

Sift

Uncertain

0.028

Sift4G

Benign

0.39

Polyphen

0.063

Vest4

0.27

MVP

0.043

MPC

0.049

ClinPred

0.0079

GERP RS

3.7

Varity_R

0.035

gMVP

0.24

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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