Genetic Variant NM_014112.5:c.2893C>T (chr8-115415015-G-A) – ACMG Classification: Likely_pathogenic (8 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM2PM5PP3_ModeratePP5_Moderate

The NM_014112.5(TRPS1):c.2893C>T(p.Arg965Cys) 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 Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R965H) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Consequence

TRPS1
NM_014112.5 missense

Scores

Clinical Significance

Pathogenic criteria provided, single submitter P:2O:1

Conservation

PhyloP100: 9.60

Publications

9 publications found

Variant links:

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

TRPS1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: 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.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.841

PP5

Variant 8-115415015-G-A is Pathogenic according to our data. 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.

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TRPS1	NM_014112.5	MANE Select	c.2893C>T	p.Arg965Cys	missense	Exon 7 of 7	NP_054831.2	Q9UHF7-2
TRPS1	NM_001282903.3		c.2872C>T	p.Arg958Cys	missense	Exon 7 of 7	NP_001269832.1
TRPS1	NM_001282902.3		c.2866C>T	p.Arg956Cys	missense	Exon 6 of 6	NP_001269831.1	Q9UHF7-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TRPS1	ENST00000395715.8	TSL:1 MANE Select	c.2893C>T	p.Arg965Cys	missense	Exon 7 of 7	ENSP00000379065.3	Q9UHF7-2
TRPS1	ENST00000220888.9	TSL:1	c.2854C>T	p.Arg952Cys	missense	Exon 6 of 6	ENSP00000220888.5	Q9UHF7-1
TRPS1	ENST00000917131.1		c.2893C>T	p.Arg965Cys	missense	Exon 8 of 8	ENSP00000587190.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00

AC:

AN:

210112

AF XY:

0.00

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

ClinVar submissions

Significance:Pathogenic

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Trichorhinophalangeal dysplasia type I (2)

Trichorhinophalangeal dysplasia type I;C1860823:Trichorhinophalangeal syndrome, type III (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.97

BayesDel_addAF

Pathogenic

0.54

BayesDel_noAF

Pathogenic

0.53

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.25

Eigen

Pathogenic

0.76

Eigen_PC

Pathogenic

0.80

FATHMM_MKL

Uncertain

0.91

LIST_S2

Uncertain

0.97

M_CAP

Pathogenic

0.40

MetaRNN

Pathogenic

0.84

MetaSVM

Pathogenic

1.1

MutationAssessor

Benign

1.0

PhyloP100

9.6

PrimateAI

Pathogenic

0.90

PROVEAN

Benign

-2.3

REVEL

Pathogenic

0.82

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.61

MutPred

0.53

Loss of MoRF binding (P = 0.0102)

MVP

0.96

MPC

1.8

ClinPred

0.97

GERP RS

5.6

Varity_R

0.42

gMVP

0.89

Mutation Taster

=4/96

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over