chr1-40862055-C-A

Variant names:

• chr1-40862055-C-A
• rs1056967075
• NM_133467.3:c.73G>T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4 BS2

The NM_133467.3(CITED4):​c.73G>T​(p.Gly25Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00004 in 1,324,692 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G25V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000019 (0 hom.)
• Consequence: CITED4 NM_133467.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.261
• Publications: 0 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: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.35138425).
• BS2: High AC in GnomAd4 at 31 AD gene.

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.73G>T	p.Gly25Cys	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.73G>T	p.Gly25Cys	missense	Exon 1 of 1	ENSP00000361721.2	Q96RK1

Frequencies

GnomAD3 genomes AF: 0.000205 AC: 31 AN: 151374 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000726

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000148

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000315 AC: 1 AN: 31796 AF XY: 0.0000510

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000188 AC: 22 AN: 1173318 Hom.: 0 Cov.: 32 AF XY: 0.0000105 AC XY: 6 AN XY: 573054

African (AFR) AF: 0.000850 AC: 20 AN: 23528

American (AMR) AF: 0.0000758 AC: 1 AN: 13186

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16930

East Asian (EAS) AF: 0.00 AC: 0 AN: 25456

South Asian (SAS) AF: 0.0000204 AC: 1 AN: 48948

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 26920

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3372

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 968388

Other (OTH) AF: 0.00 AC: 0 AN: 46590

GnomAD4 genome AF: 0.000205 AC: 31 AN: 151374 Hom.: 0 Cov.: 32 AF XY: 0.000216 AC XY: 16 AN XY: 73920

African (AFR) AF: 0.000726 AC: 30 AN: 41322

American (AMR) AF: 0.00 AC: 0 AN: 15208

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5120

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10358

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000148 AC: 1 AN: 67780

Other (OTH) AF: 0.00 AC: 0 AN: 2076

Alfa AF: 0.000214 Hom.: 0

Bravo AF: 0.000219

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0083	T
Eigen	Benign	-0.14
Eigen_PC	Benign	-0.32
FATHMM_MKL	Benign	0.23	N
LIST_S2	Benign	0.47	T
M_CAP	Pathogenic	0.87	D
MetaRNN	Benign	0.35	T
MetaSVM	Benign	-0.79	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		0.26
PrimateAI	Pathogenic	0.89	D
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.12
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.032	D
Polyphen		0.97	D
Vest4		0.27
MutPred		0.47		Loss of methylation at R30 (P = 0.1616)
MVP		0.57
MPC		1.9
ClinPred		0.75	D
GERP RS		1.4
PromoterAI		0.025	Neutral
Varity_R		0.35
gMVP		0.44
Mutation Taster		=94/6	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: rs1056967075; hg19: chr1-41327727; COSMIC: COSV65468509; COSMIC: COSV65468509;