19-45816181-A-C

Variant names:

• chr19-45816181-A-C
• rs751719892
• NM_004819.3:c.3357T>G

Variant summary

Our verdict is Likely benign. Variant got -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. 13/22 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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.42

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]

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• BS2: High AC in GnomAdExome4 at 25 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SYMPK	NM_004819.3	c.3357T>G	p.Asp1119Glu	missense_variant, splice_region_variant	Exon 26 of 27	ENST00000245934.12	NP_004810.2
SYMPK	XM_011527354.2	c.3357T>G	p.Asp1119Glu	missense_variant, splice_region_variant	Exon 27 of 28		XP_011525656.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SYMPK	ENST00000245934.12	c.3357T>G	p.Asp1119Glu	missense_variant, splice_region_variant	Exon 26 of 27	1	NM_004819.3	ENSP00000245934.7

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.0000643 AC: 9 AN: 139886 Hom.: 0 AF XY: 0.0000783 AC XY: 6 AN XY: 76606

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 SAS exome AF: 0.000456

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000182 AC: 25 AN: 1374790 Hom.: 1 Cov.: 33 AF XY: 0.0000266 AC XY: 18 AN XY: 675450

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000299

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000353

GnomAD4 genome Cov.: 31

ExAC AF: 0.0000443 AC: 5

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 15, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3357T>G (p.D1119E) alteration is located in exon 26 (coding exon 25) of the SYMPK gene. This alteration results from a T to G substitution at nucleotide position 3357, causing the aspartic acid (D) at amino acid position 1119 to be replaced by a glutamic acid (E). 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	0.065
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	0.30
DANN	Benign	0.81
DEOGEN2	Benign	0.050	T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.028	N
LIST_S2	Benign	0.61	T
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.015	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.81	L
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-0.15	N
REVEL	Benign	0.072
Sift	Benign	0.21	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.21
MutPred		0.10		Loss of stability (P = 0.1776);
MVP		0.068
MPC		0.045
ClinPred		0.066	T
GERP RS		-9.0
Varity_R		0.053
gMVP		0.074

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

LitVar

Other links and lift over

dbSNP: rs751719892; hg19: chr19-46319439;