5-40681705-T-C

Variant names:

• chr5-40681705-T-C
• rs778925464
• NM_000958.3:c.712T>C

Variant summary

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

The NM_000958.3(PTGER4):​c.712T>C​(p.Ser238Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000698 in 1,432,772 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 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. S238T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: PTGER4 NM_000958.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.226
• Publications: 0 publications found

Genes affected

PTGER4 (HGNC:9596): (prostaglandin E receptor 4) The protein encoded by this gene is a member of the G-protein coupled receptor family. This protein is one of four receptors identified for prostaglandin E2 (PGE2). This receptor can activate T-cell factor signaling. It has been shown to mediate PGE2 induced expression of early growth response 1 (EGR1), regulate the level and stability of cyclooxygenase-2 mRNA, and lead to the phosphorylation of glycogen synthase kinase-3. Knockout studies in mice suggest that this receptor may be involved in the neonatal adaptation of circulatory system, osteoporosis, as well as initiation of skin immune responses. [provided by RefSeq, Jul 2008]

TTC33 (HGNC:29959): (tetratricopeptide repeat domain 33)

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=0.17354864).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000958.3. 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
	PTGER4	NM_000958.3	MANE Select	c.712T>C	p.Ser238Pro	missense	Exon 2 of 3	NP_000949.1	P35408

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PTGER4	ENST00000302472.4	TSL:1 MANE Select	c.712T>C	p.Ser238Pro	missense	Exon 2 of 3	ENSP00000302846.3	P35408
	PTGER4	ENST00000512578.1	TSL:1	n.216T>C		non_coding_transcript_exon	Exon 1 of 2
	PTGER4	ENST00000963428.1		c.171+541T>C		intron	N/A	ENSP00000633487.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000505 AC: 1 AN: 197826 AF XY: 0.00000905

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: 0.0000117

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.98e-7 AC: 1 AN: 1432772 Hom.: 0 Cov.: 31 AF XY: 0.00000141 AC XY: 1 AN XY: 711596

African (AFR) AF: 0.00 AC: 0 AN: 32818

American (AMR) AF: 0.00 AC: 0 AN: 41808

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25524

East Asian (EAS) AF: 0.00 AC: 0 AN: 38688

South Asian (SAS) AF: 0.00 AC: 0 AN: 84730

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 41812

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5718

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1102232

Other (OTH) AF: 0.0000168 AC: 1 AN: 59442

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.031	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	13
DANN	Uncertain	0.99
DEOGEN2	Benign	0.096	T
Eigen	Benign	-0.59
Eigen_PC	Benign	-0.68
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.24	T
M_CAP	Uncertain	0.22	D
MetaRNN	Benign	0.17	T
MetaSVM	Benign	-0.29	T
MutationAssessor	Benign	0.75	N
PhyloP100		-0.23
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-0.10	N
REVEL	Benign	0.24
Sift	Benign	0.36	T
Sift4G	Benign	0.29	T
Polyphen		0.77	P
Vest4		0.11
MutPred		0.31		Loss of glycosylation at S238 (P = 0.0113)
MVP		0.83
MPC		1.5
ClinPred		0.57	D
GERP RS		1.5
Varity_R		0.18
gMVP		0.55
Mutation Taster		=90/10	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: rs778925464; hg19: chr5-40681807;