rs121908434

Positions:

• chr8-115414593-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PVS1_Strong PM2 PP5

The ENST00000395715.8(TRPS1):​c.3315C>G​(p.Tyr1105Ter) 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 (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TRPS1 ENST00000395715.8 stop_gained
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 2.50

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 7 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. There are 9 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 8-115414593-G-C is Pathogenic according to our data. Variant chr8-115414593-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 5576.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TRPS1	NM_014112.5	c.3315C>G	p.Tyr1105Ter	stop_gained	7/7	ENST00000395715.8	NP_054831.2
TRPS1	NM_001282903.3	c.3294C>G	p.Tyr1098Ter	stop_gained	7/7		NP_001269832.1
TRPS1	NM_001282902.3	c.3288C>G	p.Tyr1096Ter	stop_gained	6/6		NP_001269831.1
TRPS1	NM_001330599.2	c.3276C>G	p.Tyr1092Ter	stop_gained	6/6		NP_001317528.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TRPS1	ENST00000395715.8	c.3315C>G	p.Tyr1105Ter	stop_gained	7/7	1	NM_014112.5	ENSP00000379065	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Trichorhinophalangeal dysplasia type I Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

May 01, 2001

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.51
CADD	Pathogenic	38
DANN	Uncertain	0.99
Eigen	Pathogenic	0.73
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Benign	0.72	D
MutationTaster	Benign	1.0	A;A;A;A
Vest4		0.81, 0.89, 0.83, 0.92
ClinPred		1.0	D
GERP RS		4.8

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: rs121908434; hg19: chr8-116426821;