4-84638915-CT-CTTTT

Variant names:

• chr4-84638915-C-CTTT
• rs761209404
• NM_001263.4:c.811-5_811-3dupTTT

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PVS1_Moderate BP6

The NM_001263.4(CDS1):​c.811-5_811-3dupTTT variant causes a splice acceptor, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000206 in 1,472,732 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.00019 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00021 (0 hom.)
• Consequence: CDS1 NM_001263.4 splice_acceptor, intron
• Clinical Significance: Likely benign no assertion criteria provided B:1
• 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 1 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 8.3, offset of 0 (no position change), new splice context is: tatttgccctttttttttAGttg. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
• BP6: Variant 4-84638915-C-CTTT is Benign according to our data. Variant chr4-84638915-C-CTTT is described in ClinVar as Likely_benign. ClinVar VariationId is 3051171.Status of the report is no_assertion_criteria_provided, 0 stars.

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.811-5_811-3dupTTT		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_811-8insTTT		splice_region intron	N/A	ENSP00000295887.5	Q92903
	CDS1	ENST00000891571.1		c.907-9_907-8insTTT		splice_region intron	N/A	ENSP00000561630.1
	CDS1	ENST00000959938.1		c.907-9_907-8insTTT		splice_region intron	N/A	ENSP00000629997.1

Frequencies

GnomAD3 genomes AF: 0.000192 AC: 29 AN: 150824 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000974

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: 0.000369

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000176 AC: 37 AN: 209900 AF XY: 0.000183

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000445

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000485

Gnomad NFE exome AF: 0.000324

Gnomad OTH exome AF: 0.000415

GnomAD4 exome AF: 0.000208 AC: 275 AN: 1321808 Hom.: 0 Cov.: 20 AF XY: 0.000194 AC XY: 128 AN XY: 659262

African (AFR) AF: 0.0000686 AC: 2 AN: 29140

American (AMR) AF: 0.0000315 AC: 1 AN: 31704

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 36688

South Asian (SAS) AF: 0.00 AC: 0 AN: 66486

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49344

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

European-Non Finnish (NFE) AF: 0.000254 AC: 261 AN: 1026698

Other (OTH) AF: 0.000204 AC: 11 AN: 53924

GnomAD4 genome AF: 0.000192 AC: 29 AN: 150924 Hom.: 0 Cov.: 31 AF XY: 0.000149 AC XY: 11 AN XY: 73702

African (AFR) AF: 0.0000971 AC: 4 AN: 41190

American (AMR) AF: 0.00 AC: 0 AN: 15126

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5126

South Asian (SAS) AF: 0.00 AC: 0 AN: 4784

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10188

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 286

European-Non Finnish (NFE) AF: 0.000369 AC: 25 AN: 67750

Other (OTH) AF: 0.00 AC: 0 AN: 2096

Alfa AF: 0.000217 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	CDS1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.9
Mutation Taster		=100/0	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs761209404; hg19: chr4-85560068;