19-45815999-G-A

Variant names:

• chr19-45815999-G-A
• rs1240648306
• NM_004819.3:c.3539C>T

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.3539C>T​(p.Pro1180Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 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. P1180R) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SYMPK NM_004819.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.98
• 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=0.052292407).

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.3539C>T	p.Pro1180Leu	missense	Exon 26 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.3539C>T	p.Pro1180Leu	missense	Exon 26 of 27	ENSP00000245934.7	Q92797-1
	SYMPK	ENST00000876458.1		c.3602C>T	p.Pro1201Leu	missense	Exon 26 of 27	ENSP00000546517.1
	SYMPK	ENST00000876454.1		c.3599C>T	p.Pro1200Leu	missense	Exon 26 of 27	ENSP00000546513.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00 AC: 0 AN: 220600 AF XY: 0.00

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 Cov.: 36

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	14
DANN	Benign	0.93
DEOGEN2	Benign	0.052	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.99
FATHMM_MKL	Benign	0.092	N
LIST_S2	Benign	0.71	T
M_CAP	Benign	0.0050	T
MetaRNN	Benign	0.052	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.20	N
PhyloP100		3.0
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-0.26	N
REVEL	Benign	0.051
Sift	Uncertain	0.019	D
Sift4G	Benign	0.14	T
Polyphen		0.0	B
Vest4		0.21
MutPred		0.12		Loss of glycosylation at P1180 (P = 0.0176)
MVP		0.043
MPC		0.047
ClinPred		0.070	T
GERP RS		2.6
Varity_R		0.066
gMVP		0.11
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs1240648306; hg19: chr19-46319257;