8-115413684-AG-A

Variant summary

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

The NM_014112.5(TRPS1):c.*338del variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000218 in 247,600 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00024 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00019 (0 hom.)
• Consequence: TRPS1 NM_014112.5 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.360

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 nfe. gnomad4 allele frequency = 0.000237 (36/152120) while in subpopulation NFE AF= 0.000441 (30/68008). AF 95% confidence interval is 0.000317. There are 1 homozygotes in gnomad4. There are 20 alleles in male gnomad4 subpopulation. Median coverage is 32. 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 36 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TRPS1	NM_014112.5	c.*338del		3_prime_UTR_variant	7/7	ENST00000395715.8
TRPS1	NM_001282902.3	c.*338del		3_prime_UTR_variant	6/6
TRPS1	NM_001282903.3	c.*338del		3_prime_UTR_variant	7/7
TRPS1	NM_001330599.2	c.*338del		3_prime_UTR_variant	6/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TRPS1	ENST00000395715.8	c.*338del		3_prime_UTR_variant	7/7	1	NM_014112.5	A1
TRPS1	ENST00000220888.9	c.*338del		3_prime_UTR_variant	6/6	1		P4
TRPS1	ENST00000640765.1	c.*338del		3_prime_UTR_variant	6/6	2		P4

Frequencies

GnomAD3 genomes AF: 0.000237 AC: 36 AN: 152120 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000656

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: 0.000441

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000189 AC: 18 AN: 95480 Hom.: 0 Cov.: 0 AF XY: 0.000180 AC XY: 9 AN XY: 50132

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000300

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.000237 AC: 36 AN: 152120 Hom.: 1 Cov.: 32 AF XY: 0.000269 AC XY: 20 AN XY: 74324

Gnomad4 AFR AF: 0.000121

Gnomad4 AMR AF: 0.0000656

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000441

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000108 Hom.: 0

Bravo AF: 0.000170

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Trichorhinophalangeal syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

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: rs530055629; hg19: chr8-116425912;