8-115586972-T-G

Variant names:

• chr8-115586972-T-G
• rs2293889
• NM_014112.5:c.2700+29A>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_014112.5(TRPS1):​c.2700+29A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.608 in 1,613,052 control chromosomes in the GnomAD database, including 303,785 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.70 (38329 hom., cov: 33)
  • Exomes 𝑓: 0.60 (265456 hom.)
• Consequence: TRPS1 NM_014112.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -1.57
• Publications: 106 publications found

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 Gene-Disease associations (from GenCC):

• trichorhinophalangeal syndrome type I

  Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
• trichorhinophalangeal syndrome, type III

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• trichorhinophalangeal syndrome type I or III

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.71).
• BP6: Variant 8-115586972-T-G is Benign according to our data. Variant chr8-115586972-T-G is described in ClinVar as Benign. ClinVar VariationId is 260331.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.883 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014112.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRPS1	NM_014112.5	MANE Select	c.2700+29A>C		intron	N/A	NP_054831.2
	TRPS1	NM_001282903.3		c.2679+29A>C		intron	N/A	NP_001269832.1
	TRPS1	NM_001282902.3		c.2673+29A>C		intron	N/A	NP_001269831.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRPS1	ENST00000395715.8	TSL:1 MANE Select	c.2700+29A>C		intron	N/A	ENSP00000379065.3
	TRPS1	ENST00000220888.9	TSL:1	c.2661+29A>C		intron	N/A	ENSP00000220888.5
	TRPS1	ENST00000519674.1	TSL:1	c.2661+29A>C		intron	N/A	ENSP00000429174.1

Frequencies

GnomAD3 genomes AF: 0.696 AC: 105889 AN: 152040 Hom.: 38266 Cov.: 33

Gnomad AFR AF: 0.890

Gnomad AMI AF: 0.479

Gnomad AMR AF: 0.688

Gnomad ASJ AF: 0.603

Gnomad EAS AF: 0.829

Gnomad SAS AF: 0.664

Gnomad FIN AF: 0.734

Gnomad MID AF: 0.643

Gnomad NFE AF: 0.575

Gnomad OTH AF: 0.683

GnomAD2 exomes AF: 0.651 AC: 159956 AN: 245820 AF XY: 0.643

Gnomad AFR exome AF: 0.897

Gnomad AMR exome AF: 0.671

Gnomad ASJ exome AF: 0.588

Gnomad EAS exome AF: 0.838

Gnomad FIN exome AF: 0.715

Gnomad NFE exome AF: 0.577

Gnomad OTH exome AF: 0.630

GnomAD4 exome AF: 0.598 AC: 874033 AN: 1460894 Hom.: 265456 Cov.: 54 AF XY: 0.598 AC XY: 434856 AN XY: 726778

African (AFR) AF: 0.898 AC: 30070 AN: 33468

American (AMR) AF: 0.674 AC: 30158 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.584 AC: 15253 AN: 26136

East Asian (EAS) AF: 0.790 AC: 31363 AN: 39688

South Asian (SAS) AF: 0.639 AC: 55126 AN: 86204

European-Finnish (FIN) AF: 0.704 AC: 37221 AN: 52838

Middle Eastern (MID) AF: 0.650 AC: 3664 AN: 5640

European-Non Finnish (NFE) AF: 0.570 AC: 633497 AN: 1111830

Other (OTH) AF: 0.624 AC: 37681 AN: 60366

GnomAD4 genome AF: 0.697 AC: 106004 AN: 152158 Hom.: 38329 Cov.: 33 AF XY: 0.704 AC XY: 52357 AN XY: 74408

African (AFR) AF: 0.891 AC: 37002 AN: 41544

American (AMR) AF: 0.688 AC: 10507 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.603 AC: 2093 AN: 3470

East Asian (EAS) AF: 0.829 AC: 4275 AN: 5158

South Asian (SAS) AF: 0.663 AC: 3193 AN: 4818

European-Finnish (FIN) AF: 0.734 AC: 7776 AN: 10596

Middle Eastern (MID) AF: 0.634 AC: 185 AN: 292

European-Non Finnish (NFE) AF: 0.575 AC: 39083 AN: 67984

Other (OTH) AF: 0.689 AC: 1453 AN: 2110

Alfa AF: 0.614 Hom.: 89121

Bravo AF: 0.703

Asia WGS AF: 0.760 AC: 2641 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Nov 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Trichorhinophalangeal dysplasia type I Benign:1

Sep 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Trichorhinophalangeal syndrome, type III Benign:1

Sep 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
CADD	Benign	1.2
DANN	Benign	0.66
PhyloP100		-1.6
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2293889; hg19: chr8-116599199; COSMIC: COSV107278033; COSMIC: COSV107278033;