chr4-84635255-T-TA

Variant names:

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

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 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

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

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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 id is 3043841.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDS1	NM_001263.4	c.723-4dupA		splice_region_variant, intron_variant	Intron 7 of 12	ENST00000295887.6	NP_001254.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDS1	ENST00000295887.6	c.723-9_723-8insA		splice_region_variant, intron_variant	Intron 7 of 12	1	NM_001263.4	ENSP00000295887.5

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

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

Gnomad4 AFR exome AF: 0.00144

Gnomad4 AMR exome AF: 0.000141

Gnomad4 ASJ exome AF: 0.0000470

Gnomad4 EAS exome AF: 0.000161

Gnomad4 SAS exome AF: 0.000265

Gnomad4 FIN exome AF: 0.0000466

Gnomad4 NFE exome AF: 0.0000781

Gnomad4 OTH exome AF: 0.000305

GnomAD4 genome AF: 0.000464 AC: 70 AN: 150810 Hom.: 0 Cov.: 31 AF XY: 0.000516 AC XY: 38 AN XY: 73688

Gnomad4 AFR AF: 0.00127

Gnomad4 AMR AF: 0.000726

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000582

Gnomad4 SAS AF: 0.000209

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000443

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

CDS1-related disorder Benign:1

Jan 14, 2020

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

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

Publications

LitVar

Other links and lift over

dbSNP: rs748866234; hg19: chr4-85556408;