rs1554596328

Positions:

• chr8-115604792-T-TA

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.1176_1177insT​(p.Asn393Ter) 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/exons	MANE	UniProt
TRPS1	NM_014112.5	c.1176_1177insT	p.Asn393Ter	frameshift_variant	4/7	ENST00000395715.8
TRPS1	NM_001282902.3	c.1149_1150insT	p.Asn384Ter	frameshift_variant	3/6
TRPS1	NM_001282903.3	c.1155_1156insT	p.Asn386Ter	frameshift_variant	4/7
TRPS1	NM_001330599.2	c.1137_1138insT	p.Asn380Ter	frameshift_variant	3/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TRPS1	ENST00000395715.8	c.1176_1177insT	p.Asn393Ter	frameshift_variant	4/7	1	NM_014112.5	A1

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

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Sep 04, 2018

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

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Oct 20, 2022

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 438449). This variant is also known as 1137–1138insT. This premature translational stop signal has been observed in individual(s) with trichorhinophalangeal syndrome (PMID: 11112658, 25792522). This variant is not present in population databases (gnomAD no frequency). 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). -

Trichorhinophalangeal dysplasia type I Other:1

not provided, no classification provided

literature only

GeneReviews

-

- -

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;