X-72302171-A-G

Variant names:

• chrX-72302171-A-G
• NM_001144887.2:c.134T>C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001144887.2(CITED1):​c.134T>C​(p.Leu45Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 24)
• Consequence: CITED1 NM_001144887.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.46

Genes affected

CITED1 (HGNC:1986): (Cbp/p300 interacting transactivator with Glu/Asp rich carboxy-terminal domain 1) This gene encodes a member of the CREB-binding protein/p300-interacting transactivator with Asp/Glu-rich C-terminal domain (CITED) family of proteins. The encoded protein, also known as melanocyte-specific gene 1, may function as a transcriptional coactivator and may play a role in pigmentation of melanocytes. Alternatively spliced transcript variants have been described. [provided by RefSeq, Jan 2009]

ENSG00000285547 (HGNC:):

PIN4 (HGNC:8992): (peptidylprolyl cis/trans isomerase, NIMA-interacting 4) This gene encodes a member of the parvulin subfamily of the peptidyl-prolyl cis/trans isomerase protein family. The encoded protein catalyzes the isomerization of peptidylprolyl bonds, and may play a role in the cell cycle, chromatin remodeling, and/or ribosome biogenesis. The encoded protein may play an additional role in the mitochondria. [provided by RefSeq, Dec 2009]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.963

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CITED1	NM_001144887.2	c.134T>C	p.Leu45Pro	missense_variant	Exon 3 of 3	ENST00000651998.1	NP_001138359.1
CITED1	NM_001144885.2	c.212T>C	p.Leu71Pro	missense_variant	Exon 4 of 4		NP_001138357.1
CITED1	NM_001144886.2	c.134T>C	p.Leu45Pro	missense_variant	Exon 3 of 3		NP_001138358.1
CITED1	NM_004143.4	c.134T>C	p.Leu45Pro	missense_variant	Exon 3 of 3		NP_004134.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CITED1	ENST00000651998.1	c.134T>C	p.Leu45Pro	missense_variant	Exon 3 of 3		NM_001144887.2	ENSP00000499148.1
ENSG00000285547	ENST00000648922.1	c.1310T>C	p.Leu437Pro	missense_variant	Exon 12 of 12			ENSP00000497072.1

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 24

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 01, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.212T>C (p.L71P) alteration is located in exon 4 (coding exon 3) of the CITED1 gene. This alteration results from a T to C substitution at nucleotide position 212, causing the leucine (L) at amino acid position 71 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.53
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.36
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.32	.;.;T;T;T;T;T;.;.
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.77	.;T;T;.;.;T;T;T;T
M_CAP	Pathogenic	0.72	D
MetaRNN	Pathogenic	0.96	D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	-0.21	T
MutationAssessor	Uncertain	2.1	.;.;M;M;M;.;.;.;.
PrimateAI	Uncertain	0.62	T
PROVEAN	Uncertain	-3.0	D;D;D;D;D;D;D;D;.
REVEL	Pathogenic	0.74
Sift	Uncertain	0.0010	D;D;D;D;D;D;D;D;.
Sift4G	Uncertain	0.0050	D;D;D;D;D;.;.;.;.
Polyphen		1.0	D;D;D;D;D;.;.;.;.
Vest4		0.94
MutPred		0.83		.;.;Loss of sheet (P = 0.0126);Loss of sheet (P = 0.0126);Loss of sheet (P = 0.0126);Loss of sheet (P = 0.0126);.;.;.;
MVP		1.0
MPC		0.95
ClinPred		0.99	D
GERP RS		5.4
Varity_R		0.71
gMVP		0.89

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-71522021;