1-40862075-G-A

Variant names:

• chr1-40862075-G-A
• rs866248556
• NM_133467.3:c.53C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_133467.3(CITED4):​c.53C>T​(p.Pro18Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000854 in 1,170,566 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. P18R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 8.5e-7 (0 hom.)
• Consequence: CITED4 NM_133467.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.501
• Publications: 1 publications found

Genes affected

CITED4 (HGNC:18696): (Cbp/p300 interacting transactivator with Glu/Asp rich carboxy-terminal domain 4) The protein encoded by this intronless gene belongs to the CITED family of transcriptional coactivators that bind to several proteins, including CREB-binding protein (CBP) and p300, via a conserved 32 aa C-terminal motif, and regulate gene transcription. This protein also interacts with transcription factor AP2 (TFAP2), and thus may function as a co-activator for TFAP2. Hypermethylation and transcriptional downregulation of this gene has been observed in oligodendroglial tumors with deletions of chromosomal arms 1p and 19q, and associated with longer recurrence-free and overall survival of patients with oligodendroglial tumors. [provided by RefSeq, Aug 2011]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15682286).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_133467.3. 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
	CITED4	NM_133467.3	MANE Select	c.53C>T	p.Pro18Leu	missense	Exon 1 of 1	NP_597724.1	Q96RK1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CITED4	ENST00000372638.4	TSL:6 MANE Select	c.53C>T	p.Pro18Leu	missense	Exon 1 of 1	ENSP00000361721.2	Q96RK1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 8.54e-7 AC: 1 AN: 1170566 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 571240

⚠️ 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: 23308

American (AMR) AF: 0.00 AC: 0 AN: 11918

Ashkenazi Jewish (ASJ) AF: 0.0000607 AC: 1 AN: 16472

East Asian (EAS) AF: 0.00 AC: 0 AN: 25610

South Asian (SAS) AF: 0.00 AC: 0 AN: 47882

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 26834

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3392

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 968572

Other (OTH) AF: 0.00 AC: 0 AN: 46578

⚠️ 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 Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.0075	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	21
DANN	Benign	0.87
DEOGEN2	Benign	0.0039	T
Eigen	Benign	-0.84
Eigen_PC	Benign	-0.80
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.62	T
M_CAP	Pathogenic	0.59	D
MetaRNN	Benign	0.16	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.6	L
PhyloP100		0.50
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	-0.97	N
REVEL	Benign	0.092
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0050	D
Polyphen		0.34	B
Vest4		0.084
MutPred		0.50		Loss of glycosylation at P18 (P = 0.0128)
MVP		0.18
MPC		2.0
ClinPred		0.55	D
GERP RS		2.2
PromoterAI		-0.036	Neutral
Varity_R		0.20
gMVP		0.40
Mutation Taster		=96/4	polymorphism

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: rs866248556; hg19: chr1-41327747;