19-45815640-G-T

Variant names:

• chr19-45815640-G-T
• rs764275989
• NM_004819.3:c.3745C>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_004819.3(SYMPK):​c.3745C>A​(p.Pro1249Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,458,554 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P1249S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 28)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: SYMPK NM_004819.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.262
• Publications: 0 publications found

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

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0609999).

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.3745C>A	p.Pro1249Thr	missense	Exon 27 of 27	NP_004810.2	Q92797-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SYMPK	ENST00000245934.12	TSL:1 MANE Select	c.3745C>A	p.Pro1249Thr	missense	Exon 27 of 27	ENSP00000245934.7	Q92797-1
	SYMPK	ENST00000876458.1		c.3808C>A	p.Pro1270Thr	missense	Exon 27 of 27	ENSP00000546517.1
	SYMPK	ENST00000876454.1		c.3805C>A	p.Pro1269Thr	missense	Exon 27 of 27	ENSP00000546513.1

Frequencies

GnomAD3 genomes Cov.: 28

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1458554 Hom.: 0 Cov.: 48 AF XY: 0.00 AC XY: 0 AN XY: 725426

African (AFR) AF: 0.00 AC: 0 AN: 33378

American (AMR) AF: 0.00 AC: 0 AN: 44274

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26044

East Asian (EAS) AF: 0.00 AC: 0 AN: 39628

South Asian (SAS) AF: 0.0000117 AC: 1 AN: 85732

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52388

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5748

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111128

Other (OTH) AF: 0.00 AC: 0 AN: 60234

GnomAD4 genome Cov.: 28

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.058
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	11
DANN	Benign	0.44
DEOGEN2	Benign	0.059	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.087	N
LIST_S2	Benign	0.77	T
M_CAP	Benign	0.0031	T
MetaRNN	Benign	0.061	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.2	L
PhyloP100		0.26
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-0.60	N
REVEL	Benign	0.034
Sift	Benign	0.34	T
Sift4G	Pathogenic	0.0	D
Polyphen		0.0050	B
Vest4		0.20
MutPred		0.085		Gain of phosphorylation at P1249 (P = 0.0208)
MVP		0.043
MPC		0.050
ClinPred		0.11	T
GERP RS		-4.0
PromoterAI		0.22	Neutral
Varity_R		0.038
gMVP		0.14
Mutation Taster		=98/2	polymorphism

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

Other links and lift over

dbSNP: rs764275989; hg19: chr19-46318898;