rs28939069

Variant names:

• chr8-115415015-G-A
• rs28939069
• NM_014112.5:c.2893C>T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PP3_Moderate PP5_Moderate

The NM_014112.5(TRPS1):​c.2893C>T​(p.Arg965Cys) variant causes a missense change involving the alteration of a conserved nucleotide. 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 Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TRPS1 NM_014112.5 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2 O:1
• Conservation: PhyloP100: 9.60

Genes affected

TRPS1 (HGNC:12340): (transcriptional repressor GATA binding 1) This gene encodes a transcription factor that represses GATA-regulated genes and binds to a dynein light chain protein. Binding of the encoded protein to the dynein light chain protein affects binding to GATA consensus sequences and suppresses its transcriptional activity. Defects in this gene are a cause of tricho-rhino-phalangeal syndrome (TRPS) types I-III. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PM1: In a cross_link Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO2) (size 0) in uniprot entity TRPS1_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.841
• PP5: Variant 8-115415015-G-A is Pathogenic according to our data. Variant chr8-115415015-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 5579.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRPS1	NM_014112.5	c.2893C>T	p.Arg965Cys	missense_variant	Exon 7 of 7	ENST00000395715.8	NP_054831.2
TRPS1	NM_001282903.3	c.2872C>T	p.Arg958Cys	missense_variant	Exon 7 of 7		NP_001269832.1
TRPS1	NM_001282902.3	c.2866C>T	p.Arg956Cys	missense_variant	Exon 6 of 6		NP_001269831.1
TRPS1	NM_001330599.2	c.2854C>T	p.Arg952Cys	missense_variant	Exon 6 of 6		NP_001317528.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TRPS1	ENST00000395715.8	c.2893C>T	p.Arg965Cys	missense_variant	Exon 7 of 7	1	NM_014112.5	ENSP00000379065.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

Trichorhinophalangeal dysplasia type I Pathogenic:1 Other:1

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Feb 01, 2004

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Trichorhinophalangeal dysplasia type I;C1860823:Trichorhinophalangeal syndrome, type III Pathogenic:1

Jan 15, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 965 of the TRPS1 protein (p.Arg965Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with trichorhinophalangeal syndrome (PMID: 14560312, 17854380, 25792522, 28244134). It has also been observed to segregate with disease in related individuals. This variant is also known as c.2854C>T (p.Arg952Cys). ClinVar contains an entry for this variant (Variation ID: 5579). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt TRPS1 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects TRPS1 function (PMID: 14560312). This variant disrupts the p.Arg965 amino acid residue in TRPS1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 14560312). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.53
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.25	T;.;T;.;.
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.97	D;D;.;D;D
M_CAP	Pathogenic	0.40	D
MetaRNN	Pathogenic	0.84	D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	1.0	L;.;L;.;.
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	-2.3	.;N;N;N;N
REVEL	Pathogenic	0.82
Sift	Pathogenic	0.0	.;D;D;D;D
Sift4G	Pathogenic	0.0	.;D;D;D;D
Polyphen		1.0	D;D;D;.;D
Vest4		0.61, 0.62, 0.56, 0.59
MutPred		0.53		Loss of MoRF binding (P = 0.0102);.;Loss of MoRF binding (P = 0.0102);.;.;
MVP		0.96
MPC		1.8
ClinPred		0.97	D
GERP RS		5.6
Varity_R		0.42
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

LitVar

Other links and lift over

dbSNP: rs28939069; hg19: chr8-116427243; COSMIC: COSV55228014;