chr4-84583420-C-T

Variant names:

• chr4-84583420-C-T
• NM_001263.4:c.19C>T

Variant summary

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

The NM_001263.4(CDS1):​c.19C>T​(p.Arg7Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R7Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CDS1 NM_001263.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.728
• 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.19C>T	p.Arg7Trp	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.19C>T	p.Arg7Trp	missense	Exon 1 of 13	ENSP00000295887.5	Q92903
	CDS1	ENST00000891571.1		c.19C>T	p.Arg7Trp	missense	Exon 1 of 13	ENSP00000561630.1
	CDS1	ENST00000959938.1		c.19C>T	p.Arg7Trp	missense	Exon 1 of 12	ENSP00000629997.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 1447922 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 719992

African (AFR) AF: 0.00 AC: 0 AN: 32254

American (AMR) AF: 0.00 AC: 0 AN: 43918

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25704

East Asian (EAS) AF: 0.00 AC: 0 AN: 38180

South Asian (SAS) AF: 0.00 AC: 0 AN: 85228

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51178

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5602

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1106158

Other (OTH) AF: 0.00 AC: 0 AN: 59700

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

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	Pathogenic	0.68
BayesDel_addAF	Benign	-0.082	T
BayesDel_noAF	Benign	-0.36
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.021	T
Eigen	Benign	0.15
Eigen_PC	Benign	0.11
FATHMM_MKL	Benign	0.38	N
LIST_S2	Uncertain	0.87	D
M_CAP	Pathogenic	0.58	D
MetaRNN	Uncertain	0.59	D
MetaSVM	Benign	-0.72	T
MutationAssessor	Benign	0.0	N
PhyloP100		0.73
PrimateAI	Pathogenic	0.91	D
PROVEAN	Uncertain	-2.5	N
REVEL	Uncertain	0.32
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.31
MutPred		0.54		Loss of methylation at R7 (P = 0.0145)
MVP		0.67
MPC		0.72
ClinPred		0.82	D
GERP RS		4.1
PromoterAI		0.031	Neutral
Varity_R		0.36
gMVP		0.47
Mutation Taster		=68/32	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

hg19: chr4-85504573;