NM_004819.3:c.3700G>T

Variant names:

• chr19-45815685-C-A
• rs748866700
• NM_004819.3:c.3700G>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_004819.3(SYMPK):​c.3700G>T​(p.Gly1234Cys) 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 1,457,660 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. G1234S) 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: 0.545
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08615902).

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.3700G>T	p.Gly1234Cys	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.3700G>T	p.Gly1234Cys	missense	Exon 27 of 27	ENSP00000245934.7	Q92797-1
	SYMPK	ENST00000876458.1		c.3763G>T	p.Gly1255Cys	missense	Exon 27 of 27	ENSP00000546517.1
	SYMPK	ENST00000876454.1		c.3760G>T	p.Gly1254Cys	missense	Exon 27 of 27	ENSP00000546513.1

Frequencies

GnomAD3 genomes Cov.: 28

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1457660 Hom.: 0 Cov.: 48 AF XY: 0.00 AC XY: 0 AN XY: 725006

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

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

American (AMR) AF: 0.00 AC: 0 AN: 44070

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26004

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39626

South Asian (SAS) AF: 0.00 AC: 0 AN: 85736

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52164

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5736

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1110778

Other (OTH) AF: 0.00 AC: 0 AN: 60168

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 28

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	16
DANN	Benign	0.90
DEOGEN2	Benign	0.055	T
Eigen	Benign	-0.91
Eigen_PC	Benign	-0.96
FATHMM_MKL	Benign	0.18	N
LIST_S2	Benign	0.74	T
M_CAP	Benign	0.0063	T
MetaRNN	Benign	0.086	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.69	N
PhyloP100		0.55
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-0.20	N
REVEL	Benign	0.019
Sift	Benign	0.12	T
Sift4G	Benign	0.083	T
Polyphen		0.18	B
Vest4		0.35
MutPred		0.13		Loss of catalytic residue at A1233 (P = 0.141)
MVP		0.043
MPC		0.051
ClinPred		0.12	T
GERP RS		0.81
PromoterAI		-0.040	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.098
gMVP		0.10
Mutation Taster		=100/0	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: rs748866700; hg19: chr19-46318943; COSMIC: COSV99680094; COSMIC: COSV99680094;