1-40862030-G-T

Variant names:

• chr1-40862030-G-T
• rs1286309744
• NM_133467.3:c.98C>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_133467.3(CITED4):​c.98C>A​(p.Pro33Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000662 in 151,070 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. P33L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CITED4 NM_133467.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.575
• 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 -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.043275267).

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.98C>A	p.Pro33Gln	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.98C>A	p.Pro33Gln	missense	Exon 1 of 1	ENSP00000361721.2	Q96RK1

Frequencies

GnomAD3 genomes AF: 0.00000662 AC: 1 AN: 151070 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

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: 0.00

Gnomad OTH AF: 0.000483

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1157240 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 564092

African (AFR) AF: 0.00 AC: 0 AN: 23140

American (AMR) AF: 0.00 AC: 0 AN: 11534

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16174

East Asian (EAS) AF: 0.00 AC: 0 AN: 25104

South Asian (SAS) AF: 0.00 AC: 0 AN: 45976

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 26154

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3166

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 960248

Other (OTH) AF: 0.00 AC: 0 AN: 45744

GnomAD4 genome AF: 0.00000662 AC: 1 AN: 151070 Hom.: 0 Cov.: 32 AF XY: 0.0000136 AC XY: 1 AN XY: 73732

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

African (AFR) AF: 0.00 AC: 0 AN: 41274

American (AMR) AF: 0.00 AC: 0 AN: 15200

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3460

East Asian (EAS) AF: 0.00 AC: 0 AN: 5116

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10240

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67670

Other (OTH) AF: 0.000483 AC: 1 AN: 2072

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	14
DANN	Benign	0.84
DEOGEN2	Benign	0.0038	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.90
FATHMM_MKL	Benign	0.024	N
LIST_S2	Benign	0.40	T
M_CAP	Uncertain	0.21	D
MetaRNN	Benign	0.043	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.61	N
PhyloP100		0.57
PrimateAI	Pathogenic	0.91	D
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.066
Sift	Benign	1.0	T
Sift4G	Benign	0.35	T
Polyphen		0.0	B
Vest4		0.17
MutPred		0.32		Loss of catalytic residue at P33 (P = 0.0346)
MVP		0.067
MPC		0.82
ClinPred		0.066	T
GERP RS		2.0
PromoterAI		-0.078	Neutral
Varity_R		0.041
gMVP		0.36
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1286309744; hg19: chr1-41327702;