NM_014112.5:c.1788T>C

Variant names:

• chr8-115604181-A-G
• rs34094363
• NM_014112.5:c.1788T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_014112.5(TRPS1):​c.1788T>C​(p.Tyr596Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00324 in 1,614,062 control chromosomes in the GnomAD database, including 111 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.014 (54 hom., cov: 32)
  • Exomes 𝑓: 0.0021 (57 hom.)
• Consequence: TRPS1 NM_014112.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.694
• Publications: 5 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=-0.65).
• BP6: Variant 8-115604181-A-G is Benign according to our data. Variant chr8-115604181-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 361621.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0145 (2206/152282) while in subpopulation AFR AF = 0.0482 (2002/41560). AF 95% confidence interval is 0.0464. There are 54 homozygotes in GnomAd4. There are 1043 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 2206 AD gene.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRPS1	NM_014112.5	MANE Select	c.1788T>C	p.Tyr596Tyr	synonymous	Exon 4 of 7	NP_054831.2	Q9UHF7-2
	TRPS1	NM_001282903.3		c.1767T>C	p.Tyr589Tyr	synonymous	Exon 4 of 7	NP_001269832.1
	TRPS1	NM_001282902.3		c.1761T>C	p.Tyr587Tyr	synonymous	Exon 3 of 6	NP_001269831.1	Q9UHF7-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRPS1	ENST00000395715.8	TSL:1 MANE Select	c.1788T>C	p.Tyr596Tyr	synonymous	Exon 4 of 7	ENSP00000379065.3	Q9UHF7-2
	TRPS1	ENST00000220888.9	TSL:1	c.1749T>C	p.Tyr583Tyr	synonymous	Exon 3 of 6	ENSP00000220888.5	Q9UHF7-1
	TRPS1	ENST00000519674.1	TSL:1	c.1749T>C	p.Tyr583Tyr	synonymous	Exon 3 of 5	ENSP00000429174.1	E5RJ97

Frequencies

GnomAD3 genomes AF: 0.0145 AC: 2201 AN: 152164 Hom.: 54 Cov.: 32

Gnomad AFR AF: 0.0482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00590

Gnomad ASJ AF: 0.00432

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.000970

Gnomad OTH AF: 0.0110

GnomAD2 exomes AF: 0.00450 AC: 1121 AN: 249120 AF XY: 0.00346

Gnomad AFR exome AF: 0.0501

Gnomad AMR exome AF: 0.00496

Gnomad ASJ exome AF: 0.00437

Gnomad EAS exome AF: 0.0000557

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000938

Gnomad OTH exome AF: 0.00364

GnomAD4 exome AF: 0.00206 AC: 3017 AN: 1461780 Hom.: 57 Cov.: 32 AF XY: 0.00186 AC XY: 1354 AN XY: 727196

African (AFR) AF: 0.0518 AC: 1735 AN: 33474

American (AMR) AF: 0.00513 AC: 229 AN: 44680

Ashkenazi Jewish (ASJ) AF: 0.00517 AC: 135 AN: 26134

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39694

South Asian (SAS) AF: 0.0000927 AC: 8 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.00850 AC: 49 AN: 5768

European-Non Finnish (NFE) AF: 0.000514 AC: 572 AN: 1111970

Other (OTH) AF: 0.00477 AC: 288 AN: 60390

GnomAD4 genome AF: 0.0145 AC: 2206 AN: 152282 Hom.: 54 Cov.: 32 AF XY: 0.0140 AC XY: 1043 AN XY: 74478

African (AFR) AF: 0.0482 AC: 2002 AN: 41560

American (AMR) AF: 0.00589 AC: 90 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00432 AC: 15 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.0340 AC: 10 AN: 294

European-Non Finnish (NFE) AF: 0.000970 AC: 66 AN: 68022

Other (OTH) AF: 0.0109 AC: 23 AN: 2114

Alfa AF: 0.0102 Hom.: 18

Bravo AF: 0.0167

Asia WGS AF: 0.00346 AC: 12 AN: 3478

EpiCase AF: 0.000982

EpiControl AF: 0.00124

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Trichorhinophalangeal dysplasia type I;C1860823:Trichorhinophalangeal syndrome, type III (2)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.65
CADD	Benign	0.59
DANN	Benign	0.34
PhyloP100		-0.69
Mutation Taster		=97/3	polymorphism

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: rs34094363; hg19: chr8-116616408;