rs1554596328

Variant names:

• chr8-115604792-T-TA
• rs1554596328
• NM_014112.5:c.1176dupT

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.1176dupT​(p.Asn393fs) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2 O:1
• Conservation: PhyloP100: 0.344

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 8-115604792-T-TA is Pathogenic according to our data. Variant chr8-115604792-T-TA is described in ClinVar as [Pathogenic]. Clinvar id is 438449.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRPS1	NM_014112.5	c.1176dupT	p.Asn393fs	frameshift_variant	Exon 4 of 7	ENST00000395715.8	NP_054831.2
TRPS1	NM_001282903.3	c.1155dupT	p.Asn386fs	frameshift_variant	Exon 4 of 7		NP_001269832.1
TRPS1	NM_001282902.3	c.1149dupT	p.Asn384fs	frameshift_variant	Exon 3 of 6		NP_001269831.1
TRPS1	NM_001330599.2	c.1137dupT	p.Asn380fs	frameshift_variant	Exon 3 of 6		NP_001317528.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TRPS1	ENST00000395715.8	c.1176dupT	p.Asn393fs	frameshift_variant	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:2 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:1

Sep 04, 2018

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1176dupT variant in the TRPS1 gene has been reported previously in (as c.1137_1138insT due to alternate nomenclature) in two families with trichorhinophalangeal syndrome (Ludecke et al., 2001). The c.1176dupT variant results in the replacement of the normal codon, Asparagine 393, with a Stop codon, denoted p.Asn393Ter. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The c.1176dupT variant is not observed in large population cohorts (Lek et al., 2016). We interpret c.1176dupT as a pathogenic variant. -

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

Mar 03, 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.Asn393*) 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 individual(s) with trichorhinophalangeal syndrome (PMID: 11112658, 25792522). This variant is also known as 1137–1138insT. ClinVar contains an entry for this variant (Variation ID: 438449). For these reasons, this variant has been classified as Pathogenic. -

Trichorhinophalangeal dysplasia type I Other:1

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

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: rs1554596328; hg19: chr8-116617019;