Variant chr19-45815688-C-G details in Genebe, Genetics Data Aggregator

Variant summary

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

The NM_004819.3(SYMPK):c.3697G>C(p.Ala1233Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000304 in 1,609,654 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00017 ( 0 hom., cov: 28)

Exomes 𝑓: 0.000016 ( 0 hom. )

Consequence

SYMPK
NM_004819.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.0430

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:

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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=0.032933027).

BS2

High AC in GnomAd4 at 26 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SYMPK	NM_004819.3 linkuse as main transcript	c.3697G>C	p.Ala1233Pro	missense_variant	27/27	ENST00000245934.12
SYMPK	XM_011527354.2 linkuse as main transcript	c.3697G>C	p.Ala1233Pro	missense_variant	28/28

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SYMPK	ENST00000245934.12 linkuse as main transcript	c.3697G>C	p.Ala1233Pro	missense_variant	27/27	1	NM_004819.3	P1	Q92797-1

Frequencies

GnomAD3 genomes

AF:

0.000171

AC:

AN:

152076

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000603

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000421

AC:

AN:

237734

Hom.:

AF XY:

0.00

AC XY:

AN XY:

130194

show subpopulations

Gnomad AFR exome

AF:

0.000620

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:

0.00

Gnomad OTH exome

AF:

0.000175

GnomAD4 exome

AF:

0.0000158

AC:

AN:

1457458

Hom.:

Cov.:

AF XY:

0.0000110

AC XY:

AN XY:

724886

show subpopulations

Gnomad4 AFR exome

AF:

0.000509

Gnomad4 AMR exome

AF:

0.0000454

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.00e-7

Gnomad4 OTH exome

AF:

0.0000499

GnomAD4 genome

AF:

0.000171

AC:

AN:

152196

Hom.:

Cov.:

AF XY:

0.000121

AC XY:

AN XY:

74416

show subpopulations

Gnomad4 AFR

AF:

0.000602

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000564

Hom.:

Bravo

AF:

0.000253

ExAC

AF:

0.0000497

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 17, 2023

The c.3697G>C (p.A1233P) alteration is located in exon 27 (coding exon 26) of the SYMPK gene. This alteration results from a G to C substitution at nucleotide position 3697, causing the alanine (A) at amino acid position 1233 to be replaced by a proline (P). 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

0.079

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.49

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.056

Eigen

Benign

-0.83

Eigen_PC

Benign

-0.83

FATHMM_MKL

Benign

0.076

LIST_S2

Benign

0.63

M_CAP

Benign

0.0044

MetaRNN

Benign

0.033

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.4

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.59

PROVEAN

Benign

-0.010

REVEL

Benign

0.085

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.045

Polyphen

0.0

Vest4

0.17

MVP

0.043

MPC

0.056

ClinPred

0.073

GERP RS

3.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.16

gMVP

0.23

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