rs751298577

chr8-115587074-G-Achr8-115587074-G-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BS1_Supporting BS2

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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.88

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_benign. Variant got -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 male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TRPS1	NM_014112.5	c.2627C>T	p.Ser876Phe	missense_variant	5/7	ENST00000395715.8
TRPS1	NM_001282903.3	c.2606C>T	p.Ser869Phe	missense_variant	5/7
TRPS1	NM_001282902.3	c.2600C>T	p.Ser867Phe	missense_variant	4/6
TRPS1	NM_001330599.2	c.2588C>T	p.Ser863Phe	missense_variant	4/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TRPS1	ENST00000395715.8	c.2627C>T	p.Ser876Phe	missense_variant	5/7	1	NM_014112.5	A1

Frequencies

GnomAD3 genomes AF: 0.0000328 AC: 5 AN: 152244 Hom.: 0 Cov.: 33

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

GnomAD3 exomes AF: 0.0000161 AC: 4 AN: 248882 Hom.: 0 AF XY: 0.0000222 AC XY: 3 AN XY: 135152

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 SAS exome AF: 0.0000654

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000616 AC: 9 AN: 1461804 Hom.: 0 Cov.: 34 AF XY: 0.00000413 AC XY: 3 AN XY: 727220

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000696

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000328 AC: 5 AN: 152244 Hom.: 0 Cov.: 33 AF XY: 0.0000403 AC XY: 3 AN XY: 74374

Gnomad4 AFR AF: 0.0000482

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000264

ExAC AF: 0.00000828 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 08, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Uncertain	0.090
Cadd	Pathogenic	26
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	D
LIST_S2	Uncertain	0.94	D;D;.;D;D;D;D
M_CAP	Pathogenic	0.63	D
MetaRNN	Uncertain	0.44	T;T;T;T;T;T;T
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Benign	0.69	N;.;N;.;.;.;.
MutationTaster	Benign	0.97	D;D;D;D;D
PrimateAI	Benign	0.47	T
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	T
GERP RS		5.8
Varity_R		0.15
gMVP		0.57

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

Other links and lift over

dbSNP: rs751298577; hg19: chr8-116599301;