chr8-115587144-G-A

Position:

• chr8-115587144-G-A

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The ENST00000395715.8(TRPS1):​c.2557C>T​(p.Arg853Ter) variant causes a stop gained change involving the alteration of a non-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 (★). Synonymous variant affecting the same amino acid position (i.e. R853R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: TRPS1 ENST00000395715.8 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:3 O:1
• Conservation: PhyloP100: 0.232

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 Pathogenic. Variant got 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 8-115587144-G-A is Pathogenic according to our data. Variant chr8-115587144-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 5573.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr8-115587144-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TRPS1	NM_014112.5	c.2557C>T	p.Arg853Ter	stop_gained	5/7	ENST00000395715.8	NP_054831.2
TRPS1	NM_001282903.3	c.2536C>T	p.Arg846Ter	stop_gained	5/7		NP_001269832.1
TRPS1	NM_001282902.3	c.2530C>T	p.Arg844Ter	stop_gained	4/6		NP_001269831.1
TRPS1	NM_001330599.2	c.2518C>T	p.Arg840Ter	stop_gained	4/6		NP_001317528.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TRPS1	ENST00000395715.8	c.2557C>T	p.Arg853Ter	stop_gained	5/7	1	NM_014112.5	ENSP00000379065	A1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

Trichorhinophalangeal dysplasia type I Pathogenic:1 Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 2000	- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jun 02, 2021

Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 27535533, 25792522, 10615131, 25525159) -

TRPS1-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 16, 2024

The TRPS1 c.2557C>T variant is predicted to result in premature protein termination (p.Arg853*). This variant has been reported to be causative for Tricho-Rhino-Phalangeal syndrome I (Momeni et al. 2000. PubMed ID: 10615131, referred as p.Arg840*). This variant has not been reported in a large population database, indicating this variant is rare. Nonsense variants in TRPS1 are expected to be pathogenic. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.29
CADD	Pathogenic	33
DANN	Uncertain	0.99
Eigen	Benign	-0.039
Eigen_PC	Benign	-0.31
FATHMM_MKL	Benign	0.15	N
MutationTaster	Benign	1.0	A;A;A;A;A
Vest4		0.98, 0.98, 0.98, 0.95
GERP RS		1.6

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: rs121908432; hg19: chr8-116599371; COSMIC: COSV55236172;