chr1-40862054-C-A

Variant names:

• chr1-40862054-C-A
• rs999060496
• NM_133467.3:c.74G>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.74G>T​(p.Gly25Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000393 in 1,323,914 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. G25C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000018 (0 hom.)
• Consequence: CITED4 NM_133467.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.53
• 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=0.28977594).
• 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.74G>T	p.Gly25Val	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.74G>T	p.Gly25Val	missense	Exon 1 of 1	ENSP00000361721.2	Q96RK1

Frequencies

GnomAD3 genomes AF: 0.000205 AC: 31 AN: 151390 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: 0.00 AC: 0 AN: 31138 AF XY: 0.00

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: 0.0000179 AC: 21 AN: 1172524 Hom.: 0 Cov.: 32 AF XY: 0.00000873 AC XY: 5 AN XY: 572642

African (AFR) AF: 0.000851 AC: 20 AN: 23498

American (AMR) AF: 0.0000767 AC: 1 AN: 13044

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16872

East Asian (EAS) AF: 0.00 AC: 0 AN: 25448

South Asian (SAS) AF: 0.00 AC: 0 AN: 48846

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 26882

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3348

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 968040

Other (OTH) AF: 0.00 AC: 0 AN: 46546

GnomAD4 genome AF: 0.000205 AC: 31 AN: 151390 Hom.: 0 Cov.: 32 AF XY: 0.000216 AC XY: 16 AN XY: 73926

African (AFR) AF: 0.000726 AC: 30 AN: 41314

American (AMR) AF: 0.00 AC: 0 AN: 15212

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5144

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10344

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 312

European-Non Finnish (NFE) AF: 0.0000148 AC: 1 AN: 67790

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	0.13
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	20
DANN	Uncertain	0.98
DEOGEN2	Benign	0.0062	T
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.40
FATHMM_MKL	Benign	0.28	N
LIST_S2	Benign	0.51	T
M_CAP	Pathogenic	0.87	D
MetaRNN	Benign	0.29	T
MetaSVM	Benign	-0.83	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		1.5
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	0.15	N
REVEL	Benign	0.080
Sift	Uncertain	0.0030	D
Sift4G	Benign	0.11	T
Polyphen		0.62	P
Vest4		0.30
MutPred		0.45		Loss of catalytic residue at G25 (P = 0.1214)
MVP		0.50
MPC		1.9
ClinPred		0.63	D
GERP RS		3.3
PromoterAI		-0.0087	Neutral
Varity_R		0.13
gMVP		0.43
Mutation Taster		=91/9	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: rs999060496; hg19: chr1-41327726;