rs1554596418

Positions:

• chr8-115604926-C-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Moderate PP5_Moderate

The NM_014112.5(TRPS1):​c.1043G>T​(p.Cys348Phe) 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 (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TRPS1 NM_014112.5 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.84

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 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.885
• PP5: Variant 8-115604926-C-A is Pathogenic according to our data. Variant chr8-115604926-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 522955.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TRPS1	NM_014112.5	c.1043G>T	p.Cys348Phe	missense_variant	4/7	ENST00000395715.8	NP_054831.2
TRPS1	NM_001282903.3	c.1022G>T	p.Cys341Phe	missense_variant	4/7		NP_001269832.1
TRPS1	NM_001282902.3	c.1016G>T	p.Cys339Phe	missense_variant	3/6		NP_001269831.1
TRPS1	NM_001330599.2	c.1004G>T	p.Cys335Phe	missense_variant	3/6		NP_001317528.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TRPS1	ENST00000395715.8	c.1043G>T	p.Cys348Phe	missense_variant	4/7	1	NM_014112.5	ENSP00000379065.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Trichorhinophalangeal dysplasia type I Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Dec 18, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.070
CADD	Pathogenic	32
DANN	Uncertain	0.99
DEOGEN2	Benign	0.40	T;.;T;.;.;T;.
Eigen	Pathogenic	0.73
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D;D;.;D;D;D;D
M_CAP	Benign	0.025	T
MetaRNN	Pathogenic	0.88	D;D;D;D;D;D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.97	L;.;L;.;.;.;.
PrimateAI	Pathogenic	0.91	D
PROVEAN	Uncertain	-2.5	.;D;N;D;N;D;D
REVEL	Uncertain	0.58
Sift	Pathogenic	0.0	.;D;D;D;D;D;D
Sift4G	Pathogenic	0.0	.;D;D;D;D;D;D
Polyphen		1.0	D;D;D;.;D;.;.
Vest4		0.93, 0.92, 0.97, 0.94, 0.91
MutPred		0.78		Loss of sheet (P = 0.0037);.;Loss of sheet (P = 0.0037);.;.;Loss of sheet (P = 0.0037);.;
MVP		0.34
MPC		0.60
ClinPred		0.96	D
GERP RS		5.7
Varity_R		0.78
gMVP		0.93

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs1554596418; hg19: chr8-116617153;