4-84635255-T-A

Variant names:

• chr4-84635255-T-A
• rs376285323
• NM_001263.4:c.723-9T>A

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_001263.4(CDS1):​c.723-9T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00233 in 1,297,760 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.0012 (2 hom., cov: 31)
  • Exomes 𝑓: 0.0025 (4 hom.)
• Consequence: CDS1 NM_001263.4 intron
• Scores: Splicing: ADA: 0.0008073
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: -4.07
• 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: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 4-84635255-T-A is Benign according to our data. Variant chr4-84635255-T-A is described in ClinVar as Benign. ClinVar VariationId is 3049585.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

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.723-9T>A		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.723-9T>A		intron	N/A	ENSP00000295887.5	Q92903
	CDS1	ENST00000891571.1		c.819-9T>A		intron	N/A	ENSP00000561630.1
	CDS1	ENST00000959938.1		c.819-9T>A		intron	N/A	ENSP00000629997.1

Frequencies

GnomAD3 genomes AF: 0.00119 AC: 180 AN: 150680 Hom.: 2 Cov.: 31

Gnomad AFR AF: 0.00125

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000793

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00135

Gnomad SAS AF: 0.0121

Gnomad FIN AF: 0.000193

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.000695

Gnomad OTH AF: 0.000974

GnomAD2 exomes AF: 0.00394 AC: 705 AN: 179016 AF XY: 0.00452

Gnomad AFR exome AF: 0.00229

Gnomad AMR exome AF: 0.00251

Gnomad ASJ exome AF: 0.00180

Gnomad EAS exome AF: 0.00178

Gnomad FIN exome AF: 0.00347

Gnomad NFE exome AF: 0.00236

Gnomad OTH exome AF: 0.00389

GnomAD4 exome AF: 0.00248 AC: 2845 AN: 1146974 Hom.: 4 Cov.: 18 AF XY: 0.00270 AC XY: 1565 AN XY: 580164

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

African (AFR) AF: 0.00226 AC: 55 AN: 24286

American (AMR) AF: 0.00201 AC: 57 AN: 28354

Ashkenazi Jewish (ASJ) AF: 0.000613 AC: 13 AN: 21224

East Asian (EAS) AF: 0.00277 AC: 103 AN: 37156

South Asian (SAS) AF: 0.0122 AC: 871 AN: 71536

European-Finnish (FIN) AF: 0.00119 AC: 51 AN: 42868

Middle Eastern (MID) AF: 0.00302 AC: 14 AN: 4634

European-Non Finnish (NFE) AF: 0.00181 AC: 1573 AN: 867848

Other (OTH) AF: 0.00220 AC: 108 AN: 49068

⚠️ 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: 0.00119 AC: 179 AN: 150786 Hom.: 2 Cov.: 31 AF XY: 0.00144 AC XY: 106 AN XY: 73670

African (AFR) AF: 0.00125 AC: 51 AN: 40940

American (AMR) AF: 0.000792 AC: 12 AN: 15156

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3462

East Asian (EAS) AF: 0.00136 AC: 7 AN: 5156

South Asian (SAS) AF: 0.0119 AC: 57 AN: 4792

European-Finnish (FIN) AF: 0.000193 AC: 2 AN: 10358

Middle Eastern (MID) AF: 0.00342 AC: 1 AN: 292

European-Non Finnish (NFE) AF: 0.000695 AC: 47 AN: 67642

Other (OTH) AF: 0.000963 AC: 2 AN: 2076

Alfa AF: 0.00325 Hom.: 1

Bravo AF: 0.000967

ClinVar

ClinVar submissions

Significance: 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
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.33
DANN	Benign	0.14
PhyloP100		-4.1
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00081
dbscSNV1_RF	Benign	0.084
SpliceAI score (max)		0.080		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: rs376285323; hg19: chr4-85556408; COSMIC: COSV55690093;