8-115409420-CCCTTT-C

Variant summary

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

The NM_014112.5(TRPS1):c.*4598_*4602del variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000743 in 152,068 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00074 (1 hom., cov: 31)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TRPS1 NM_014112.5 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.06

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 amr. gnomad4 allele frequency = 0.000743 (113/152068) while in subpopulation AMR AF= 0.00171 (26/15238). AF 95% confidence interval is 0.0012. There are 1 homozygotes in gnomad4. There are 63 alleles in male gnomad4 subpopulation. Median coverage is 31. 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 113 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TRPS1	NM_014112.5	c.*4598_*4602del		3_prime_UTR_variant	7/7	ENST00000395715.8
TRPS1	NM_001282902.3	c.*4598_*4602del		3_prime_UTR_variant	6/6
TRPS1	NM_001282903.3	c.*4598_*4602del		3_prime_UTR_variant	7/7
TRPS1	NM_001330599.2	c.*4598_*4602del		3_prime_UTR_variant	6/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TRPS1	ENST00000395715.8	c.*4598_*4602del		3_prime_UTR_variant	7/7	1	NM_014112.5	A1
TRPS1	ENST00000640765.1	c.*4598_*4602del		3_prime_UTR_variant	6/6	2		P4

Frequencies

GnomAD3 genomes AF: 0.000744 AC: 113 AN: 151952 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.000218

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00171

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00405

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000471

Gnomad OTH AF: 0.00144

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 10 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 6

Gnomad4 NFE exome AF: 0.00

GnomAD4 genome AF: 0.000743 AC: 113 AN: 152068 Hom.: 1 Cov.: 31 AF XY: 0.000848 AC XY: 63 AN XY: 74334

Gnomad4 AFR AF: 0.000217

Gnomad4 AMR AF: 0.00171

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00405

Gnomad4 NFE AF: 0.000471

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000486 Hom.: 0

Bravo AF: 0.000468

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

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Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs755682849; hg19: chr8-116421648;