rs121908431

Positions:

• chr8-115604099-G-A
• chr8-115604099-G-C

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.1870C>T​(p.Arg624*) 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:4 O:1
• Conservation: PhyloP100: -0.467

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 8-115604099-G-A is Pathogenic according to our data. Variant chr8-115604099-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 5570.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-115604099-G-A is described in Lovd as [Likely_pathogenic]. Variant chr8-115604099-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TRPS1	NM_014112.5	c.1870C>T	p.Arg624*	stop_gained	4/7	ENST00000395715.8	NP_054831.2
TRPS1	NM_001282903.3	c.1849C>T	p.Arg617*	stop_gained	4/7		NP_001269832.1
TRPS1	NM_001282902.3	c.1843C>T	p.Arg615*	stop_gained	3/6		NP_001269831.1
TRPS1	NM_001330599.2	c.1831C>T	p.Arg611*	stop_gained	3/6		NP_001317528.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TRPS1	ENST00000395715.8	c.1870C>T	p.Arg624*	stop_gained	4/7	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:4 Other:1

Revision: criteria provided, multiple submitters, no conflicts

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	- -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 31, 2023

The c.1870C>T (p.R624*) alteration, located in exon 4 (coding exon 3) of the TRPS1 gene, consists of a C to T substitution at nucleotide position 1870. This changes the amino acid from an arginine (R) to a stop codon at amino acid position 624. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This mutation (also designated as p.R611* in the literature) has been identified in several individuals with trichorhinophalangeal syndrome and segregated with disease in one family (Momeni, 2000; Maas, 2015). In another family, the proband presented with brachydactyly, short stature, bulbous nose, long flat philtrum, and thin upper lip; her sister with similar skeletal issues and brachydactyly as well as her mother with brachydactyly were also heterozygous for this variant (Karaca, 2019). Based on the available evidence, this alteration is classified as pathogenic. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Mar 27, 2024

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 (gnomAD); Also known as R611X and R615X; This variant is associated with the following publications: (PMID: 25525159, 25792522, 10615131, 30914275, 32347565, 15616909) -

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

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 03, 2023

This sequence change creates a premature translational stop signal (p.Arg624*) 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 clinical features of trichorhinophalangeal syndrome (PMID: 10615131, 30914275). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 5570). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Benign	-0.24
CADD	Benign	21
DANN	Benign	0.89
Eigen	Benign	-0.66
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.18	N
Vest4		0.88, 0.88, 0.96, 0.90
GERP RS		-8.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs121908431; hg19: chr8-116616326; COSMIC: COSV55246225;