rs1057518972

Variant names:

• chr8-115418359-C-G
• rs1057518972
• NM_014112.5:c.2794G>C

Your query was ambiguous. Multiple possible variants found:

• chr8-115418359-C-G
• chr8-115418359-C-T

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM1 PM2 PM5 PP3_Strong

The NM_014112.5(TRPS1):​c.2794G>C​(p.Ala932Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A932T) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TRPS1 NM_014112.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.71
• 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: Pathogenic. The variant received 10 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 uncertain in NM_014112.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr8-115418359-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 374202.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.954

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRPS1	NM_014112.5	c.2794G>C	p.Ala932Pro	missense_variant	Exon 6 of 7	ENST00000395715.8	NP_054831.2
TRPS1	NM_001282903.3	c.2773G>C	p.Ala925Pro	missense_variant	Exon 6 of 7		NP_001269832.1
TRPS1	NM_001282902.3	c.2767G>C	p.Ala923Pro	missense_variant	Exon 5 of 6		NP_001269831.1
TRPS1	NM_001330599.2	c.2755G>C	p.Ala919Pro	missense_variant	Exon 5 of 6		NP_001317528.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TRPS1	ENST00000395715.8	c.2794G>C	p.Ala932Pro	missense_variant	Exon 6 of 7	1	NM_014112.5	ENSP00000379065.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.57
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.87	D;.;D;.;.
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Pathogenic	0.99	D;D;.;D;D
M_CAP	Pathogenic	0.56	D
MetaRNN	Pathogenic	0.95	D;D;D;D;D
MetaSVM	Uncertain	0.70	D
MutationAssessor	Pathogenic	3.1	M;.;M;.;.
PhyloP100		7.7
PrimateAI	Pathogenic	0.94	D
PROVEAN	Uncertain	-3.1	.;D;D;D;D
REVEL	Pathogenic	0.94
Sift	Pathogenic	0.0	.;D;D;D;D
Sift4G	Pathogenic	0.0	.;D;D;D;D
Polyphen		1.0	D;D;D;.;D
Vest4		0.88, 0.95, 0.95, 0.84
MutPred		0.78		Gain of relative solvent accessibility (P = 0.0249);.;Gain of relative solvent accessibility (P = 0.0249);.;.;
MVP		0.92
MPC		1.8
ClinPred		1.0	D
GERP RS		5.8
Varity_R		0.96
gMVP		1.0
Mutation Taster		=2/98	disease causing

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: rs1057518972; hg19: chr8-116430587;