rs528617646

Variant names:

• chr4-84635256-A-T
• rs528617646
• NM_001263.4:c.723-8A>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001263.4(CDS1):​c.723-8A>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00395 in 1,358,350 control chromosomes in the GnomAD database, including 89 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.020 (78 hom., cov: 31)
  • Exomes 𝑓: 0.0020 (11 hom.)
• Consequence: CDS1 NM_001263.4 splice_region, intron
• Scores: Splicing: ADA: 0.00001159
• Clinical Significance: Likely benign criteria provided, single submitter 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: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BP6: Variant 4-84635256-A-T is Benign according to our data. Variant chr4-84635256-A-T is described in ClinVar as Likely_benign. ClinVar VariationId is 775994.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0645 is higher than 0.05.

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.723-8A>T		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.723-8A>T		splice_region intron	N/A	ENSP00000295887.5	Q92903
	CDS1	ENST00000891571.1		c.819-8A>T		splice_region intron	N/A	ENSP00000561630.1
	CDS1	ENST00000959938.1		c.819-8A>T		splice_region intron	N/A	ENSP00000629997.1

Frequencies

GnomAD3 genomes AF: 0.0196 AC: 2886 AN: 147490 Hom.: 76 Cov.: 31

Gnomad AFR AF: 0.0667

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00635

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000592

Gnomad SAS AF: 0.000641

Gnomad FIN AF: 0.000426

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00138

Gnomad OTH AF: 0.00985

GnomAD2 exomes AF: 0.00489 AC: 895 AN: 182854 AF XY: 0.00366

Gnomad AFR exome AF: 0.0514

Gnomad AMR exome AF: 0.00281

Gnomad ASJ exome AF: 0.000620

Gnomad EAS exome AF: 0.000618

Gnomad FIN exome AF: 0.00136

Gnomad NFE exome AF: 0.00122

Gnomad OTH exome AF: 0.00345

GnomAD4 exome AF: 0.00205 AC: 2477 AN: 1210764 Hom.: 11 Cov.: 19 AF XY: 0.00195 AC XY: 1192 AN XY: 610430

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

African (AFR) AF: 0.0503 AC: 1286 AN: 25566

American (AMR) AF: 0.00370 AC: 105 AN: 28392

Ashkenazi Jewish (ASJ) AF: 0.0000924 AC: 2 AN: 21638

East Asian (EAS) AF: 0.000299 AC: 11 AN: 36844

South Asian (SAS) AF: 0.000583 AC: 42 AN: 72078

European-Finnish (FIN) AF: 0.00101 AC: 44 AN: 43744

Middle Eastern (MID) AF: 0.00143 AC: 7 AN: 4884

European-Non Finnish (NFE) AF: 0.000855 AC: 792 AN: 926358

Other (OTH) AF: 0.00367 AC: 188 AN: 51260

⚠️ 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: 0.0196 AC: 2890 AN: 147586 Hom.: 78 Cov.: 31 AF XY: 0.0194 AC XY: 1394 AN XY: 71774

African (AFR) AF: 0.0666 AC: 2674 AN: 40162

American (AMR) AF: 0.00634 AC: 94 AN: 14816

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3422

East Asian (EAS) AF: 0.000594 AC: 3 AN: 5052

South Asian (SAS) AF: 0.000643 AC: 3 AN: 4666

European-Finnish (FIN) AF: 0.000426 AC: 4 AN: 9398

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 290

European-Non Finnish (NFE) AF: 0.00138 AC: 92 AN: 66824

Other (OTH) AF: 0.00975 AC: 20 AN: 2052

Alfa AF: 0.00664 Hom.: 5

Bravo AF: 0.0213

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.55
DANN	Benign	0.26
PhyloP100		-2.3
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000012
dbscSNV1_RF	Benign	0.014
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: rs528617646; hg19: chr4-85556409; COSMIC: COSV55687743;