1-40984966-A-G

Variant names:

• chr1-40984966-A-G
• rs150868456
• NM_001905.4:c.312A>G

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Moderate BP6_Moderate BP7 BS2

The NM_001905.4(CTPS1):​c.312A>G​(p.Gly104Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000153 in 1,584,144 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Synonymous variant affecting the same amino acid position (i.e. G104G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00080 (2 hom., cov: 33)
  • Exomes 𝑓: 0.000084 (0 hom.)
• Consequence: CTPS1 NM_001905.4 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 0.0360
• Publications: 0 publications found

Genes affected

CTPS1 (HGNC:2519): (CTP synthase 1) This gene encodes an enzyme responsible for the catalytic conversion of UTP (uridine triphosphate) to CTP (cytidine triphospate). This reaction is an important step in the biosynthesis of phospholipids and nucleic acids. Activity of this proten is important in the immune system, and loss of function of this gene has been associated with immunodeficiency. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2014]

CTPS1 Gene-Disease associations (from GenCC):

• combined immunodeficiency due to CTPS1 deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Orphanet

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.44).
• BP6: Variant 1-40984966-A-G is Benign according to our data. Variant chr1-40984966-A-G is described in ClinVar as Likely_benign. ClinVar VariationId is 541959.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.036 with no splicing effect.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001905.4. 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
	CTPS1	NM_001905.4	MANE Select	c.312A>G	p.Gly104Gly	synonymous	Exon 3 of 19	NP_001896.2	P17812-1
	CTPS1	NR_125440.2		n.459A>G		non_coding_transcript_exon	Exon 3 of 18

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CTPS1	ENST00000650070.2	MANE Select	c.312A>G	p.Gly104Gly	synonymous	Exon 3 of 19	ENSP00000497602.1	P17812-1
	CTPS1	ENST00000372616.1	TSL:2	c.312A>G	p.Gly104Gly	synonymous	Exon 2 of 18	ENSP00000361699.1	P17812-1
	CTPS1	ENST00000470271.6	TSL:3	c.312A>G	p.Gly104Gly	synonymous	Exon 3 of 19	ENSP00000497901.2	P17812-1

Frequencies

GnomAD3 genomes AF: 0.000723 AC: 110 AN: 152208 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00258

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

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: 0.00

Gnomad OTH AF: 0.000955

GnomAD2 exomes AF: 0.000179 AC: 43 AN: 240368 AF XY: 0.000115

Gnomad AFR exome AF: 0.00220

Gnomad AMR exome AF: 0.0000974

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000270

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000838 AC: 120 AN: 1431818 Hom.: 0 Cov.: 30 AF XY: 0.0000706 AC XY: 50 AN XY: 708002

African (AFR) AF: 0.00225 AC: 74 AN: 32900

American (AMR) AF: 0.0000947 AC: 4 AN: 42230

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25690

East Asian (EAS) AF: 0.00 AC: 0 AN: 38806

South Asian (SAS) AF: 0.0000242 AC: 2 AN: 82556

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52978

Middle Eastern (MID) AF: 0.000882 AC: 5 AN: 5670

European-Non Finnish (NFE) AF: 0.0000165 AC: 18 AN: 1091974

Other (OTH) AF: 0.000288 AC: 17 AN: 59014

GnomAD4 genome AF: 0.000801 AC: 122 AN: 152326 Hom.: 2 Cov.: 33 AF XY: 0.000752 AC XY: 56 AN XY: 74488

African (AFR) AF: 0.00286 AC: 119 AN: 41566

American (AMR) AF: 0.0000653 AC: 1 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68032

Other (OTH) AF: 0.000945 AC: 2 AN: 2116

Alfa AF: 0.000365 Hom.: 0

Bravo AF: 0.000816

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Combined immunodeficiency due to CTPS1 deficiency (1)
-	-	1	CTPS1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.44
CADD	Benign	7.2
DANN	Benign	0.71
PhyloP100		0.036
Mutation Taster		=71/29	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs150868456; hg19: chr1-41450638;