rs886040971

Variant names:

• chr8-115604339-G-A
• rs886040971
• NM_014112.5:c.1630C>T

Your query was ambiguous. Multiple possible variants found:

• chr8-115604339-G-A
• chr8-115604339-G-C
• chr8-115604339-G-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_014112.5(TRPS1):​c.1630C>T​(p.Arg544*) 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 (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TRPS1 NM_014112.5 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:11 O:2
• Conservation: PhyloP100: 1.34

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 18 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 8-115604339-G-A is Pathogenic according to our data. Variant chr8-115604339-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 267746.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-115604339-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRPS1	NM_014112.5	c.1630C>T	p.Arg544*	stop_gained	Exon 4 of 7	ENST00000395715.8	NP_054831.2
TRPS1	NM_001282903.3	c.1609C>T	p.Arg537*	stop_gained	Exon 4 of 7		NP_001269832.1
TRPS1	NM_001282902.3	c.1603C>T	p.Arg535*	stop_gained	Exon 3 of 6		NP_001269831.1
TRPS1	NM_001330599.2	c.1591C>T	p.Arg531*	stop_gained	Exon 3 of 6		NP_001317528.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TRPS1	ENST00000395715.8	c.1630C>T	p.Arg544*	stop_gained	Exon 4 of 7	1	NM_014112.5	ENSP00000379065.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:11 Other:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Trichorhinophalangeal dysplasia type I Pathogenic:4 Other:1

Jan 15, 2016

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has been previously reported (PMID: 11112658, 23451857) and was seen once in our laboratory de novo in a 3-year-old female with dysmorphisms, developmental delay, autism, hypotonia, relative macrocephaly, failure to thrive, congenital diaphragmatic hernia, recurrent umbilical hernia, pectus carinatum, joint laxity. She also carried a de novo nonsense variant in FBN1. -

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Department of Medical Genetics, Sanjay Gandhi Post Graduate Institute of Medical Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Analysis of the data showed a heterozygous sequence variant in TRPS1 gene. It is predicted as pathogenic by MutationTaster. This variant is classified as pathogenic which shows strong evidence of pathogenicity according to ACMG guidelines (Richards et al., 2015). Sanger sequencing confirmed the variation in proband and parents were wild type for the same variation. -

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GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Oct 09, 2019

Knight Diagnostic Laboratories, Oregon Health and Sciences University

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 16, 2020

Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:4

May 25, 2016

Clinical Genetics and Genomics, Karolinska University Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

TRPS1: PVS1, PM2, PS4:Moderate -

Jan 18, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Identified in multiple unrelated individuals with trichorhinophalangeal syndrome (reported as c.1591C>T due to alternate nomenclature) in published literature (Ludecke et al., 2001; Sohn et al., 2012); 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 in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 23451857, 25525159, 11112658, 28050602, 32502225, 22964620) -

Apr 19, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Langer-Giedion syndrome Pathogenic:1

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Institute for Genomic Statistics and Bioinformatics, University Hospital Bonn

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

TRPS1-related disorder Pathogenic:1

Jun 21, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The TRPS1 c.1630C>T variant is predicted to result in premature protein termination (p.Arg544*). This variant has been reported in individuals with tricho-rhino-phalangeal syndrome (reported as p.Arg531*, Ludecke et al. 2001. PubMed ID: 11112658; Ito et al. 2013. PubMed ID: 23451857). This variant, along with a de novo FBN1 variant was reported in one individual with a complex connective tissue phenotype (reported as de novo, Zastrow et al. 2017. PubMed ID: 28050602). 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. -

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

Dec 07, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Arg544*) in the TRPS1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in TRPS1 are known to be pathogenic (PMID: 11112658). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individuals with trichorhinophalangeal syndrome (PMID: 11112658, 22964620, 23451857, 25792522, 28050602). This variant is also known as p.Arg531*. ClinVar contains an entry for this variant (Variation ID: 267746). For these reasons, this variant has been classified as Pathogenic. -

Trichorhinophalangeal syndrome, type III Other:1

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GenomeConnect, ClinGen

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

Variant interpreted as Pathogenic and reported on 04-23-2021 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	35
DANN	Uncertain	1.0
Eigen	Uncertain	0.41
Eigen_PC	Benign	0.20
FATHMM_MKL	Uncertain	0.86	D
Vest4		0.91, 0.89, 0.89, 0.92
GERP RS		-1.7

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

Publications

LitVar

Other links and lift over

dbSNP: rs886040971; hg19: chr8-116616566; COSMIC: COSV55235791;