rs1554617580

chr8-115418421-T-C

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1 PM2 PP3_Moderate PP5_Very_Strong

The NM_014112.5(TRPS1):c.2732A>G(p.Asn911Ser) variant causes a missense change involving the alteration of a 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N911Y) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TRPS1 NM_014112.5 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:3 O:1
• Conservation: PhyloP100: 7.82

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 14 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_014112.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.912
• PP5: Variant 8-115418421-T-C is Pathogenic according to our data. Variant chr8-115418421-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 438461.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.2732A>G	p.Asn911Ser	missense_variant	6/7	ENST00000395715.8
TRPS1	NM_001282903.3	c.2711A>G	p.Asn904Ser	missense_variant	6/7
TRPS1	NM_001282902.3	c.2705A>G	p.Asn902Ser	missense_variant	5/6
TRPS1	NM_001330599.2	c.2693A>G	p.Asn898Ser	missense_variant	5/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TRPS1	ENST00000395715.8	c.2732A>G	p.Asn911Ser	missense_variant	6/7	1	NM_014112.5	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Metaphyseal chondrodysplasia Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Petrovsky National Research Centre of Surgery, The Federal Agency for Scientific Organizations

Mar 05, 2024

We observed de novo variant NM_014112:c.2732A>G (p.Asn911Ser) in the TRPS1 gene in female proband (33 y.o., Caucasian) with metaphyseal chondrodysplasia with alopecia (parenthood was not tested). No additional rare candidate variants (Class III-V of pathogenicity) were found in this proband. This variant is absent in The Genome Aggregation Database (gnomAD) v2.1.1 and v4.0.0 (Date of access with 04-03-2024). Clinvar contains an entry for this variant (Variation ID: 438461). This variant has been reported in 3 publications in patients with variable phenotypes (PMID: 31502745, 28426188, 25792522). This variants is located in zinc finger domain GATA-type AA 896-920 and alternative change NM_014112:c.2731A>T (p.Asn911Tyr) have been classified as Likely Pathogenic (ACMG: PM1, PM2, PP3, PP5). Most in silico predictors show pathogenic result of the protein change (varsome.com). In accordance with ACMG(2015) this variant is classified as Likely Pathogenic with following criteria selected: PM1, PM2, PM5_supporting, PM6, PP3, PP5. -

Trichorhinophalangeal syndrome, type III Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

3billion

May 22, 2022

The variant is not observed in the gnomAD v2.1.1 dataset. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.79; 3Cnet: 0.49). Same nucleotide change resulting in same amino acid change (ClinVar ID: VCV000438461 / PMID: 25792522) and a different missense change at the same codon (p.Asn911Tyr, ClinVar ID: VCV000438460 / PMID: 25792522) have been previously reported to be associated with TRPS1 related disorder. Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline. -

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

Likely pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jul 18, 2022

This missense change has been observed in individuals with clinical features of tricho-rhino-phalangeal syndrome (PMID: 25792522; Invitae). It has also been observed to segregate with disease in related individuals. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Asn911 amino acid residue in TRPS1. Other variant(s) that disrupt this residue have been observed in individuals with TRPS1-related conditions (PMID: 25792522), which suggests that this may be a clinically significant amino acid residue. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 438461). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 911 of the TRPS1 protein (p.Asn911Ser). -

Trichorhinophalangeal dysplasia type I Other:1

not provided, no classification provided

literature only

GeneReviews

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
Cadd	Pathogenic	27
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.69	D;.;D;.;.
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.96	D;D;.;D;D
M_CAP	Pathogenic	0.69	D
MetaRNN	Pathogenic	0.91	D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.0	M;.;M;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.83	D
Polyphen		1.0	D;D;D;.;D
Vest4		0.84, 0.96, 0.92, 0.86
MutPred		0.71		Gain of glycosylation at N898 (P = 0.0673);.;Gain of glycosylation at N898 (P = 0.0673);.;.;
MVP		0.83
MPC		1.4
ClinPred		0.98	D
GERP RS		5.7
Varity_R		0.72
gMVP		0.96

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: rs1554617580; hg19: chr8-116430649;