chr8-115414111-G-A

Position:

chr8-115414111-G-A

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4BP6BS1BS2

The NM_014112.5(TRPS1):c.3797C>T(p.Thr1266Met) variant causes a missense change. The variant allele was found at a frequency of 0.000151 in 1,613,644 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. T1266T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000072 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00016 ( 0 hom. )

Consequence

TRPS1
NM_014112.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: 5.87

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -10 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.3359738).

BP6

Variant 8-115414111-G-A is Benign according to our data. Variant chr8-115414111-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1347607.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0000724 (11/151942) while in subpopulation NFE AF= 0.000147 (10/67994). AF 95% confidence interval is 0.0000791. There are 0 homozygotes in gnomad4. There are 7 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 11 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
TRPS1	NM_014112.5 linkuse as main transcript	c.3797C>T	p.Thr1266Met	missense_variant	7/7	ENST00000395715.8
TRPS1	NM_001282903.3 linkuse as main transcript	c.3776C>T	p.Thr1259Met	missense_variant	7/7
TRPS1	NM_001282902.3 linkuse as main transcript	c.3770C>T	p.Thr1257Met	missense_variant	6/6
TRPS1	NM_001330599.2 linkuse as main transcript	c.3758C>T	p.Thr1253Met	missense_variant	6/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TRPS1	ENST00000395715.8 linkuse as main transcript	c.3797C>T	p.Thr1266Met	missense_variant	7/7	1	NM_014112.5	A1	Q9UHF7-2

Frequencies

GnomAD3 genomes

AF:

0.0000724

AC:

AN:

151942

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000683

AC:

AN:

249040

Hom.:

AF XY:

0.0000592

AC XY:

AN XY:

135092

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000580

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000124

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000159

AC:

232

AN:

1461702

Hom.:

Cov.:

AF XY:

0.000147

AC XY:

107

AN XY:

727146

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.000112

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000580

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000196

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.0000724

AC:

AN:

151942

Hom.:

Cov.:

AF XY:

0.0000944

AC XY:

AN XY:

74182

show subpopulations

Gnomad4 AFR

AF:

0.0000242

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000579

Hom.:

Bravo

AF:

0.0000604

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000120

AC:

ExAC

AF:

0.0000910

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

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

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Nov 28, 2023

This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 1266 of the TRPS1 protein (p.Thr1266Met). This variant is present in population databases (rs376875568, gnomAD 0.01%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with TRPS1-related conditions. ClinVar contains an entry for this variant (Variation ID: 1347607). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt TRPS1 protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 14, 2023

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.095

BayesDel_addAF

Benign

-0.10

BayesDel_noAF

Benign

-0.16

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.14

T;.;T;.;.

Eigen

Pathogenic

0.78

Eigen_PC

Pathogenic

0.76

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.93

D;D;.;D;D

M_CAP

Benign

0.026

MetaRNN

Benign

0.34

T;T;T;T;T

MetaSVM

Benign

-0.50

MutationAssessor

Benign

0.90

L;.;L;.;.

MutationTaster

Benign

0.99

D;D;D;D

PrimateAI

Uncertain

0.72

Polyphen

1.0

D;D;D;.;D

Vest4

0.68, 0.65, 0.62, 0.72

MVP

0.24

MPC

1.6

ClinPred

0.26

GERP RS

5.4

Varity_R

0.33

gMVP

0.40

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over