4-84583454-C-G

Variant names:

• chr4-84583454-C-G
• rs1255574180
• NM_001263.4:c.53C>G

Variant summary

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

The NM_001263.4(CDS1):​c.53C>G​(p.Ser18Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000189 in 1,584,446 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CDS1 NM_001263.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.824
• Publications: 0 publications found

Genes affected

CDS1 (HGNC:1800): (CDP-diacylglycerol synthase 1) Breakdown products of phosphoinositides are ubiquitous second messengers that function downstream of many G protein-coupled receptors and tyrosine kinases regulating cell growth, calcium metabolism, and protein kinase C activity. This gene encodes an enzyme which regulates the amount of phosphatidylinositol available for signaling by catalyzing the conversion of phosphatidic acid to CDP-diacylglycerol. This enzyme is an integral membrane protein localized to two subcellular domains, the matrix side of the inner mitochondrial membrane where it is thought to be involved in the synthesis of phosphatidylglycerol and cardiolipin and the cytoplasmic side of the endoplasmic reticulum where it functions in phosphatidylinositol biosynthesis. Two genes encoding this enzyme have been identified in humans, one mapping to human chromosome 4q21 and a second to 20p13. [provided by RefSeq, Jul 2008]

ENSG00000306033 (HGNC:58840):

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=0.15271106).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001263.4. 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
	CDS1	NM_001263.4	MANE Select	c.53C>G	p.Ser18Trp	missense	Exon 1 of 13	NP_001254.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDS1	ENST00000295887.6	TSL:1 MANE Select	c.53C>G	p.Ser18Trp	missense	Exon 1 of 13	ENSP00000295887.5	Q92903
	CDS1	ENST00000891571.1		c.53C>G	p.Ser18Trp	missense	Exon 1 of 13	ENSP00000561630.1
	CDS1	ENST00000959938.1		c.53C>G	p.Ser18Trp	missense	Exon 1 of 12	ENSP00000629997.1

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152078 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000140 AC: 2 AN: 1432368 Hom.: 0 Cov.: 30 AF XY: 0.00000141 AC XY: 1 AN XY: 710692

African (AFR) AF: 0.00 AC: 0 AN: 31940

American (AMR) AF: 0.00 AC: 0 AN: 41358

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25368

East Asian (EAS) AF: 0.00 AC: 0 AN: 37242

South Asian (SAS) AF: 0.00 AC: 0 AN: 83012

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49658

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5694

European-Non Finnish (NFE) AF: 0.00000182 AC: 2 AN: 1098906

Other (OTH) AF: 0.00 AC: 0 AN: 59190

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 152078 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74278

African (AFR) AF: 0.00 AC: 0 AN: 41432

American (AMR) AF: 0.00 AC: 0 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5146

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67992

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	19
DANN	Uncertain	0.98
DEOGEN2	Benign	0.019	T
Eigen	Benign	-0.49
Eigen_PC	Benign	-0.54
FATHMM_MKL	Benign	0.063	N
LIST_S2	Benign	0.67	T
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.15	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
PhyloP100		0.82
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.038
Sift	Uncertain	0.015	D
Sift4G	Uncertain	0.016	D
Polyphen		0.69	P
Vest4		0.24
MutPred		0.29		Loss of glycosylation at P19 (P = 0.0342)
MVP		0.54
MPC		0.66
ClinPred		0.36	T
GERP RS		2.4
PromoterAI		-0.0011	Neutral
Varity_R		0.16
gMVP		0.29
Mutation Taster		=94/6	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: rs1255574180; hg19: chr4-85504607;