rs1554617011

Positions:

• chr8-115414923-CCTCT-C

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_Strong PM2 PP5_Moderate

The NM_014112.5(TRPS1):​c.2981_2984delAGAG​(p.Glu994fs) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TRPS1 NM_014112.5 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1 O:1
• Conservation: PhyloP100: 7.64

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 Likely_pathogenic. Variant got 8 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.233 CDS is truncated, and there are 1 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 8-115414923-CCTCT-C is Pathogenic according to our data. Variant chr8-115414923-CCTCT-C is described in ClinVar as [Pathogenic]. Clinvar id is 438471.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TRPS1	NM_014112.5	c.2981_2984delAGAG	p.Glu994fs	frameshift_variant	7/7	ENST00000395715.8	NP_054831.2
TRPS1	NM_001282903.3	c.2960_2963delAGAG	p.Glu987fs	frameshift_variant	7/7		NP_001269832.1
TRPS1	NM_001282902.3	c.2954_2957delAGAG	p.Glu985fs	frameshift_variant	6/6		NP_001269831.1
TRPS1	NM_001330599.2	c.2942_2945delAGAG	p.Glu981fs	frameshift_variant	6/6		NP_001317528.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TRPS1	ENST00000395715.8	c.2981_2984delAGAG	p.Glu994fs	frameshift_variant	7/7	1	NM_014112.5	ENSP00000379065.3

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 26, 2019

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the C-terminus of the TRPS1 protein. Other variant(s) that disrupt this region (p.Ser1026Thrfs*27, p.Pro1047Leufs*6, p.Ser1142Valfs*36) have been observed in individuals with TRPS1-related conditions (PMID: 25792522). This suggests that this may be a clinically significant region of the protein. This variant has been observed in several individuals with clinical features of trichorhinophalangeal syndrome (PMID: 25792522, Invitae). The variant is also known as c.2942_2945del in the literature. ClinVar contains an entry for this variant (Variation ID: 438471). This variant is not present in population databases (ExAC no frequency). This sequence change results in a premature translational stop signal in the TRPS1 gene (p.Glu994Glyfs*7). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 1196 amino acids of the TRPS1 protein. -

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: rs1554617011; hg19: chr8-116427151;