rs767926757

Variant names:

• chr16-88804003-G-A
• rs767926757
• NM_030928.4:c.172G>A

Your query was ambiguous. Multiple possible variants found:

• chr16-88804003-G-A
• chr16-88804003-G-C
• chr16-88804003-G-T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_030928.4(CDT1):​c.172G>A​(p.Gly58Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000154 in 1,302,560 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000015 (0 hom.)
• Consequence: CDT1 NM_030928.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0860
• Publications: 0 publications found

Genes affected

CDT1 (HGNC:24576): (chromatin licensing and DNA replication factor 1) The protein encoded by this gene is involved in the formation of the pre-replication complex that is necessary for DNA replication. The encoded protein can bind geminin, which prevents replication and may function to prevent this protein from initiating replication at inappropriate origins. Phosphorylation of this protein by cyclin A-dependent kinases results in degradation of the protein. [provided by RefSeq, Mar 2011]

CDT1 Gene-Disease associations (from GenCC):

• Meier-Gorlin syndrome 4

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), G2P
• Meier-Gorlin syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 4 uncertain in NM_030928.4
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.11848879).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDT1	NM_030928.4	c.172G>A	p.Gly58Arg	missense_variant	Exon 1 of 10	ENST00000301019.9	NP_112190.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDT1	ENST00000301019.9	c.172G>A	p.Gly58Arg	missense_variant	Exon 1 of 10	1	NM_030928.4	ENSP00000301019.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000154 AC: 2 AN: 1302560 Hom.: 0 Cov.: 31 AF XY: 0.00000156 AC XY: 1 AN XY: 642490

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

African (AFR) AF: 0.00 AC: 0 AN: 25956

American (AMR) AF: 0.00 AC: 0 AN: 24156

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22498

East Asian (EAS) AF: 0.00 AC: 0 AN: 28362

South Asian (SAS) AF: 0.00 AC: 0 AN: 70870

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 31992

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3856

European-Non Finnish (NFE) AF: 0.00000192 AC: 2 AN: 1041236

Other (OTH) AF: 0.00 AC: 0 AN: 53634

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000203476), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	13
DANN	Benign	0.97
DEOGEN2	Benign	0.031	T
Eigen	Benign	-0.85
Eigen_PC	Benign	-0.95
FATHMM_MKL	Benign	0.0093	N
LIST_S2	Benign	0.38	T
M_CAP	Benign	0.057	D
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	L
PhyloP100		0.086
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-0.88	N
REVEL	Benign	0.11
Sift	Benign	0.28	T
Sift4G	Benign	0.55	T
Polyphen		0.94	P
Vest4		0.050
MutPred		0.22		Gain of methylation at G58 (P = 0.0313);
MVP		0.60
MPC		1.5
ClinPred		0.13	T
GERP RS		-1.7
PromoterAI		-0.093	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.3
Varity_R		0.073
gMVP		0.14

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs767926757; hg19: chr16-88870411;