NM_001263.4:c.723-4dupA

Variant names:

• chr4-84635255-T-TA
• rs748866234
• NM_001263.4:c.723-4dupA

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP6

The NM_001263.4(CDS1):​c.723-4dupA variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000171 in 1,301,532 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.00046 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00013 (0 hom.)
• Consequence: CDS1 NM_001263.4 splice_region, intron
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: -2.28
• 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: Likely_benign. The variant received -1 ACMG points.

• BP6: Variant 4-84635255-T-TA is Benign according to our data. Variant chr4-84635255-T-TA is described in ClinVar as Likely_benign. ClinVar VariationId is 3043841.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.723-4dupA		splice_region 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.723-9_723-8insA		splice_region intron	N/A	ENSP00000295887.5	Q92903
	CDS1	ENST00000891571.1		c.819-9_819-8insA		splice_region intron	N/A	ENSP00000561630.1
	CDS1	ENST00000959938.1		c.819-9_819-8insA		splice_region intron	N/A	ENSP00000629997.1

Frequencies

GnomAD3 genomes AF: 0.000464 AC: 70 AN: 150704 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00127

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000727

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000580

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000443

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000168 AC: 30 AN: 179016 AF XY: 0.000133

Gnomad AFR exome AF: 0.000917

Gnomad AMR exome AF: 0.000160

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000356

Gnomad FIN exome AF: 0.0000738

Gnomad NFE exome AF: 0.0000562

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000133 AC: 153 AN: 1150722 Hom.: 0 Cov.: 19 AF XY: 0.000131 AC XY: 76 AN XY: 582042

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00144 AC: 35 AN: 24354

American (AMR) AF: 0.000141 AC: 4 AN: 28430

Ashkenazi Jewish (ASJ) AF: 0.0000470 AC: 1 AN: 21276

East Asian (EAS) AF: 0.000161 AC: 6 AN: 37222

South Asian (SAS) AF: 0.000265 AC: 19 AN: 71700

European-Finnish (FIN) AF: 0.0000466 AC: 2 AN: 42936

Middle Eastern (MID) AF: 0.000646 AC: 3 AN: 4646

European-Non Finnish (NFE) AF: 0.0000781 AC: 68 AN: 870962

Other (OTH) AF: 0.000305 AC: 15 AN: 49196

⚠️ 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 AF: 0.000464 AC: 70 AN: 150810 Hom.: 0 Cov.: 31 AF XY: 0.000516 AC XY: 38 AN XY: 73688

African (AFR) AF: 0.00127 AC: 52 AN: 40940

American (AMR) AF: 0.000726 AC: 11 AN: 15160

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.000582 AC: 3 AN: 5156

South Asian (SAS) AF: 0.000209 AC: 1 AN: 4792

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10368

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.0000443 AC: 3 AN: 67650

Other (OTH) AF: 0.00 AC: 0 AN: 2076

Alfa AF: 0.00 Hom.: 1

ClinVar

ClinVar submissions

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		-2.3
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs748866234; hg19: chr4-85556408;