19-45815643-C-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2BP4_StrongBP6_Moderate

The NM_004819.3(SYMPK):​c.3742G>A​(p.Ala1248Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000186 in 1,610,104 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Likely benign (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 28)
Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

SYMPK
NM_004819.3 missense

Scores

19

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.0280
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.027315497).
BP6
Variant 19-45815643-C-T is Benign according to our data. Variant chr19-45815643-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 3323876.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SYMPKNM_004819.3 linkc.3742G>A p.Ala1248Thr missense_variant Exon 27 of 27 ENST00000245934.12 NP_004810.2 Q92797-1A0A024R0R6
SYMPKXM_011527354.2 linkc.3742G>A p.Ala1248Thr missense_variant Exon 28 of 28 XP_011525656.1 Q92797-1A0A024R0R6

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SYMPKENST00000245934.12 linkc.3742G>A p.Ala1248Thr missense_variant Exon 27 of 27 1 NM_004819.3 ENSP00000245934.7 Q92797-1

Frequencies

GnomAD3 genomes
AF:
0.00000659
AC:
1
AN:
151686
Hom.:
0
Cov.:
28
show subpopulations
Gnomad AFR
AF:
0.00
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:
0.0000948
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000413
AC:
1
AN:
242196
Hom.:
0
AF XY:
0.00000758
AC XY:
1
AN XY:
131986
show subpopulations
Gnomad AFR exome
AF:
0.0000652
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:
0.00
GnomAD4 exome
AF:
0.00000137
AC:
2
AN:
1458418
Hom.:
0
Cov.:
48
AF XY:
0.00000276
AC XY:
2
AN XY:
725388
show subpopulations
Gnomad4 AFR exome
AF:
0.0000599
Gnomad4 AMR exome
AF:
0.00
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:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.00000659
AC:
1
AN:
151686
Hom.:
0
Cov.:
28
AF XY:
0.00
AC XY:
0
AN XY:
74078
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.0000948
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000113

ClinVar

Significance: Likely benign
Submissions summary: Benign:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Benign:1
Apr 08, 2024
Ambry Genetics
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.064
BayesDel_addAF
Benign
-0.28
T
BayesDel_noAF
Benign
-0.64
CADD
Benign
5.3
DANN
Benign
0.73
DEOGEN2
Benign
0.054
T
Eigen
Benign
-1.5
Eigen_PC
Benign
-1.5
FATHMM_MKL
Benign
0.026
N
LIST_S2
Benign
0.68
T
M_CAP
Benign
0.0056
T
MetaRNN
Benign
0.027
T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
0.69
N
PrimateAI
Benign
0.46
T
PROVEAN
Benign
0.010
N
REVEL
Benign
0.028
Sift
Benign
0.78
T
Sift4G
Benign
0.53
T
Polyphen
0.0
B
Vest4
0.079
MutPred
0.030
Gain of phosphorylation at A1248 (P = 0.0227);
MVP
0.068
MPC
0.046
ClinPred
0.020
T
GERP RS
-1.1
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.0
Varity_R
0.022
gMVP
0.072

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.

Other links and lift over

dbSNP: rs1460950394; hg19: chr19-46318901; API