rs766395793

Variant names:

• chr19-45815648-G-A
• NM_004819.3:c.3737C>T

Your query was ambiguous. Multiple possible variants found:

• chr19-45815648-G-A
• chr19-45815648-G-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_004819.3(SYMPK):​c.3737C>T​(p.Thr1246Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,458,938 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 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. T1246S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 28)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: SYMPK NM_004819.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0170

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 -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.048956215).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SYMPK	NM_004819.3	c.3737C>T	p.Thr1246Ile	missense_variant	Exon 27 of 27	ENST00000245934.12	NP_004810.2
SYMPK	XM_011527354.2	c.3737C>T	p.Thr1246Ile	missense_variant	Exon 28 of 28		XP_011525656.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SYMPK	ENST00000245934.12	c.3737C>T	p.Thr1246Ile	missense_variant	Exon 27 of 27	1	NM_004819.3	ENSP00000245934.7

Frequencies

GnomAD3 genomes Cov.: 28

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1458938 Hom.: 0 Cov.: 48 AF XY: 0.00000138 AC XY: 1 AN XY: 725630

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 28

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	16
DANN	Benign	0.94
DEOGEN2	Benign	0.056	T
Eigen	Benign	-0.83
Eigen_PC	Benign	-0.72
FATHMM_MKL	Benign	0.35	N
LIST_S2	Benign	0.54	T
M_CAP	Benign	0.0042	T
MetaRNN	Benign	0.049	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.1	L
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-0.31	N
REVEL	Benign	0.055
Sift	Benign	0.037	D
Sift4G	Benign	0.088	T
Polyphen		0.0	B
Vest4		0.090
MutPred		0.10		Loss of glycosylation at T1246 (P = 0.0224);
MVP		0.043
MPC		0.049
ClinPred		0.070	T
GERP RS		2.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.043
gMVP		0.11

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-46318906;