NM_014112.5:c.3855A>C

Variant names:

• chr8-115414053-T-G
• rs1335170890
• NM_014112.5:c.3855A>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_014112.5(TRPS1):​c.3855A>C​(p.Gln1285His) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,461,502 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: TRPS1 NM_014112.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.61
• Publications: 0 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.39738256).

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.3855A>C	p.Gln1285His	missense	Exon 7 of 7	NP_054831.2	Q9UHF7-2
	TRPS1	NM_001282903.3		c.3834A>C	p.Gln1278His	missense	Exon 7 of 7	NP_001269832.1
	TRPS1	NM_001282902.3		c.3828A>C	p.Gln1276His	missense	Exon 6 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.3855A>C	p.Gln1285His	missense	Exon 7 of 7	ENSP00000379065.3	Q9UHF7-2
	TRPS1	ENST00000220888.9	TSL:1	c.3816A>C	p.Gln1272His	missense	Exon 6 of 6	ENSP00000220888.5	Q9UHF7-1
	TRPS1	ENST00000917131.1		c.3855A>C	p.Gln1285His	missense	Exon 8 of 8	ENSP00000587190.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000803 AC: 2 AN: 248988 AF XY: 0.0000148

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461502 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727066

African (AFR) AF: 0.00 AC: 0 AN: 33450

American (AMR) AF: 0.00 AC: 0 AN: 44690

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26108

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86236

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53410

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111784

Other (OTH) AF: 0.00 AC: 0 AN: 60368

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Trichorhinophalangeal dysplasia type I;C1860823:Trichorhinophalangeal syndrome, type III (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Uncertain	0.087	D
BayesDel_noAF	Uncertain	0.070
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.17	T
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.88	D
M_CAP	Pathogenic	0.31	D
MetaRNN	Benign	0.40	T
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	0.69	N
PhyloP100		6.6
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-1.1	N
REVEL	Uncertain	0.48
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.98	D
Vest4		0.45
MutPred		0.14		Gain of catalytic residue at E1274 (P = 0.0609)
MVP		0.53
MPC		1.2
ClinPred		0.65	D
GERP RS		5.4
Varity_R		0.45
gMVP		0.37
Mutation Taster		=83/17	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: rs1335170890; hg19: chr8-116426281;