rs28939070

Variant names:

• chr8-115415014-C-T
• rs28939070
• NM_014112.5:c.2894G>A

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 17P and 0B. PS3 PM2 PM5 PP3 PP5_Very_Strong

The NM_014112.5(TRPS1):​c.2894G>A​(p.Arg965His) 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 (★★). ClinVar reports functional evidence for this variant: "SCV000644696: Experimental studies have shown that this missense change affects TRPS1 function (PMID:14560312)." and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R965C) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TRPS1 NM_014112.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3 O:1
• Conservation: PhyloP100: 7.57
• Publications: 6 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 17 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000644696: Experimental studies have shown that this missense change affects TRPS1 function (PMID: 14560312).; SCV002569850: In vitro assays demonstrated primarily cytoplasmic localization and loss of nuclear localization (Elli et al., 2022; Kaiser et al., 2004)
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr8-115415015-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 5579.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.806
• PP5: Variant 8-115415014-C-T is Pathogenic according to our data. Variant chr8-115415014-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 5580.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014112.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRPS1	NM_014112.5	MANE Select	c.2894G>A	p.Arg965His	missense	Exon 7 of 7	NP_054831.2	Q9UHF7-2
	TRPS1	NM_001282903.3		c.2873G>A	p.Arg958His	missense	Exon 7 of 7	NP_001269832.1
	TRPS1	NM_001282902.3		c.2867G>A	p.Arg956His	missense	Exon 6 of 6	NP_001269831.1	Q9UHF7-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRPS1	ENST00000395715.8	TSL:1 MANE Select	c.2894G>A	p.Arg965His	missense	Exon 7 of 7	ENSP00000379065.3	Q9UHF7-2
	TRPS1	ENST00000220888.9	TSL:1	c.2855G>A	p.Arg952His	missense	Exon 6 of 6	ENSP00000220888.5	Q9UHF7-1
	TRPS1	ENST00000917131.1		c.2894G>A	p.Arg965His	missense	Exon 8 of 8	ENSP00000587190.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
1	-	-	not provided (1)
1	-	-	Trichorhinophalangeal dysplasia type I (2)
1	-	-	Trichorhinophalangeal dysplasia type I;C1860823:Trichorhinophalangeal syndrome, type III (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.86
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.51
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.22	T
Eigen	Pathogenic	0.70
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.31	D
MetaRNN	Pathogenic	0.81	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	1.0	L
PhyloP100		7.6
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-0.39	N
REVEL	Pathogenic	0.74
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.74
MutPred		0.53		Loss of MoRF binding (P = 0.0285)
MVP		0.90
MPC		1.8
ClinPred		0.93	D
GERP RS		5.6
Varity_R		0.28
gMVP		0.78
Mutation Taster		=1/99	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs28939070; hg19: chr8-116427242; COSMIC: COSV55253041;