chr8-115604954-A-AATCTG

Variant names:

• chr8-115604954-A-AATCTG
• rs1554596430
• NM_014112.5:c.1010_1014dupCAGAT

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_014112.5(TRPS1):​c.1010_1014dupCAGAT​(p.Cys339GlnfsTer27) 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 not provided (no stars). Synonymous variant affecting the same amino acid position (i.e. D338D) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TRPS1 NM_014112.5 frameshift
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: 2.48
• Publications: 0 publications found

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]

TRPS1 Gene-Disease associations (from GenCC):

• trichorhinophalangeal syndrome type I

  Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
• trichorhinophalangeal syndrome, type III

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• trichorhinophalangeal syndrome type I or III

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 10 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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRPS1	NM_014112.5	c.1010_1014dupCAGAT	p.Cys339GlnfsTer27	frameshift_variant	Exon 4 of 7	ENST00000395715.8	NP_054831.2
TRPS1	NM_001282903.3	c.989_993dupCAGAT	p.Cys332GlnfsTer27	frameshift_variant	Exon 4 of 7		NP_001269832.1
TRPS1	NM_001282902.3	c.983_987dupCAGAT	p.Cys330GlnfsTer27	frameshift_variant	Exon 3 of 6		NP_001269831.1
TRPS1	NM_001330599.2	c.971_975dupCAGAT	p.Cys326GlnfsTer27	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.1010_1014dupCAGAT	p.Cys339GlnfsTer27	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: not provided

Submissions summary: Other:1

Revision: no classification provided

Submissions by phenotype

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

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.5
Mutation Taster		=1/199	disease causing (ClinVar)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1554596430; hg19: chr8-116617181;