4-84638915-CT-CTT

Variant names:

• chr4-84638915-C-CT
• rs761209404
• NM_001263.4:c.811-3dupT

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PVS1_Moderate PM2

The NM_001263.4(CDS1):​c.811-3dupT variant causes a splice acceptor, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000227 in 1,321,794 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000023 (0 hom.)
• Consequence: CDS1 NM_001263.4 splice_acceptor, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.87
• 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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.04978355 fraction of the gene. Cryptic splice site detected, with MaxEntScore 7.9, offset of 0 (no position change), new splice context is: tttatttgccctttttttAGttg. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
• 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.811-3dupT		splice_acceptor intron	N/A	NP_001254.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDS1	ENST00000295887.6	TSL:1 MANE Select	c.811-9_811-8insT		splice_region intron	N/A	ENSP00000295887.5	Q92903
	CDS1	ENST00000891571.1		c.907-9_907-8insT		splice_region intron	N/A	ENSP00000561630.1
	CDS1	ENST00000959938.1		c.907-9_907-8insT		splice_region intron	N/A	ENSP00000629997.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000227 AC: 3 AN: 1321794 Hom.: 0 Cov.: 20 AF XY: 0.00000152 AC XY: 1 AN XY: 659254

⚠️ 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: 29138

American (AMR) AF: 0.00 AC: 0 AN: 31704

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22828

East Asian (EAS) AF: 0.00 AC: 0 AN: 36686

South Asian (SAS) AF: 0.0000150 AC: 1 AN: 66484

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49342

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4996

European-Non Finnish (NFE) AF: 9.74e-7 AC: 1 AN: 1026696

Other (OTH) AF: 0.0000185 AC: 1 AN: 53920

⚠️ 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.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.9

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: rs761209404; hg19: chr4-85560068;