Genetic Variant SYMPK:p.Asp1119Glu (chr19-45816181-A-C) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_004819.3(SYMPK):c.3357T>G(p.Asp1119Glu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000182 in 1,374,790 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.000018 ( 1 hom. )

Consequence

SYMPK
NM_004819.3 missense, splice_region

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -1.42

Publications

0 publications found

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 was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BS2

High AC in GnomAdExome4 at 25 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004819.3. 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
	SYMPK	NM_004819.3	MANE Select	c.3357T>G	p.Asp1119Glu	missense splice_region	Exon 26 of 27	NP_004810.2	Q92797-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SYMPK	ENST00000245934.12	TSL:1 MANE Select	c.3357T>G	p.Asp1119Glu	missense splice_region	Exon 26 of 27	ENSP00000245934.7	Q92797-1
SYMPK	ENST00000876458.1		c.3420T>G	p.Asp1140Glu	missense splice_region	Exon 26 of 27	ENSP00000546517.1
SYMPK	ENST00000876454.1		c.3417T>G	p.Asp1139Glu	missense splice_region	Exon 26 of 27	ENSP00000546513.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000643

AC:

AN:

139886

AF XY:

0.0000783

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS 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:

0.0000182

AC:

AN:

1374790

Hom.:

Cov.:

AF XY:

0.0000266

AC XY:

AN XY:

675450

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31282

American (AMR)

AF:

0.00

AC:

AN:

33720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23360

East Asian (EAS)

AF:

0.00

AC:

AN:

36904

South Asian (SAS)

AF:

0.000299

AC:

AN:

76882

European-Finnish (FIN)

AF:

0.00

AC:

AN:

45284

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4052

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1066690

Other (OTH)

AF:

0.0000353

AC:

AN:

56616

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.453

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ExAC

AF:

0.0000443

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.065

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.62

CADD

Benign

0.30

(source)

DANN

Benign

0.81

DEOGEN2

Benign

0.050

Eigen

Benign

-1.7

Eigen_PC

Benign

-1.7

FATHMM_MKL

Benign

0.028

LIST_S2

Benign

0.61

M_CAP

Benign

0.010

MetaRNN

Benign

0.015

MetaSVM

Benign

-0.95

MutationAssessor

Benign

0.81

PhyloP100

-1.4

PrimateAI

Uncertain

0.70

PROVEAN

Benign

-0.15

REVEL

Benign

0.072

Sift

Benign

0.21

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.21

MutPred

0.10

Loss of stability (P = 0.1776)

MVP

0.068

MPC

0.045

ClinPred

0.066

GERP RS

-9.0

Varity_R

0.053

gMVP

0.074

Mutation Taster

=89/11

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.25

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.25

Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over