rs751298577

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BS1_SupportingBS2

The NM_014112.5(TRPS1):c.2627C>T(p.Ser876Phe) variant causes a missense change. The variant allele was found at a frequency of 0.00000867 in 1,614,048 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S876Y) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000062 ( 0 hom. )

Consequence

TRPS1
NM_014112.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.88

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 was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0000328 (5/152244) while in subpopulation SAS AF = 0.000207 (1/4834). AF 95% confidence interval is 0.0000226. There are 0 homozygotes in GnomAd4. There are 3 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position FAILED quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High AC in GnomAd4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRPS1	NM_014112.5 link	c.2627C>T	p.Ser876Phe	missense_variant	Exon 5 of 7	ENST00000395715.8	NP_054831.2	Q9UHF7-2
TRPS1	NM_001282903.3 link	c.2606C>T	p.Ser869Phe	missense_variant	Exon 5 of 7		NP_001269832.1	Q9UHF7
TRPS1	NM_001282902.3 link	c.2600C>T	p.Ser867Phe	missense_variant	Exon 4 of 6		NP_001269831.1	Q9UHF7-3
TRPS1	NM_001330599.2 link	c.2588C>T	p.Ser863Phe	missense_variant	Exon 4 of 6		NP_001317528.1	Q9UHF7-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TRPS1	ENST00000395715.8 link	c.2627C>T	p.Ser876Phe	missense_variant	Exon 5 of 7	1	NM_014112.5	ENSP00000379065.3		Q9UHF7-2

Frequencies

GnomAD3 genomes

AF:

0.0000328

AC:

AN:

152244

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000161

AC:

AN:

248882

AF XY:

0.0000222

show subpopulations

Gnomad AFR exome

AF:

0.0000651

Gnomad AMR exome

AF:

0.0000290

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

AF:

0.00000616

AC:

AN:

1461804

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727220

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

AC:

AN:

33480

Gnomad4 AMR exome

AF:

0.0000224

AC:

AN:

44722

Gnomad4 ASJ exome

AF:

0.00

AC:

AN:

26136

Gnomad4 EAS exome

AF:

0.00

AC:

AN:

39692

Gnomad4 SAS exome

AF:

0.0000696

AC:

AN:

86256

Gnomad4 FIN exome

AF:

0.00

AC:

AN:

53360

Gnomad4 NFE exome

AF:

0.00

AC:

AN:

1111994

Gnomad4 Remaining exome

AF:

0.00

AC:

AN:

60396

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000328

AC:

AN:

152244

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74374

show subpopulations

Gnomad4 AFR

AF:

0.0000482

AC:

0.0000482323

AN:

0.0000482323

Gnomad4 AMR

AF:

0.000131

AC:

0.000130787

AN:

0.000130787

Gnomad4 ASJ

AF:

0.00

AC:

AN:

Gnomad4 EAS

AF:

0.00

AC:

AN:

Gnomad4 SAS

AF:

0.000207

AC:

0.000206868

AN:

0.000206868

Gnomad4 FIN

AF:

0.00

AC:

AN:

Gnomad4 NFE

AF:

0.00

AC:

AN:

Gnomad4 OTH

AF:

0.00

AC:

AN:

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000264

ExAC

AF:

0.00000828

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Dec 08, 2017

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Uncertain

0.10

BayesDel_noAF

Uncertain

0.090

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.25

T;.;T;.;.;T;.

Eigen

Uncertain

0.27

Eigen_PC

Uncertain

0.38

FATHMM_MKL

Uncertain

0.85

LIST_S2

Uncertain

0.94

D;D;.;D;D;D;D

M_CAP

Pathogenic

0.63

MetaRNN

Uncertain

0.44

T;T;T;T;T;T;T

MetaSVM

Pathogenic

1.0

MutationAssessor

Benign

0.69

N;.;N;.;.;.;.

PrimateAI

Benign

0.47

PROVEAN

Benign

-1.9

.;N;N;N;N;N;.

REVEL

Pathogenic

0.73

Sift

Uncertain

0.0010

.;D;D;D;D;D;.

Sift4G

Uncertain

0.0090

.;D;D;D;D;D;D

Polyphen

0.80

P;P;P;.;B;.;.

Vest4

0.71, 0.82, 0.50, 0.64, 0.33

MutPred

0.28

Loss of glycosylation at S863 (P = 0.0103);.;Loss of glycosylation at S863 (P = 0.0103);.;.;Loss of glycosylation at S863 (P = 0.0103);.;

MVP

0.72

MPC

0.93

ClinPred

0.18

GERP RS

5.8

Varity_R

0.15

gMVP

0.57

Mutation Taster

=8/92

disease causing

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