8-115604881-A-G

Variant names:

• chr8-115604881-A-G
• rs1554596397
• NM_014112.5:c.1088T>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_014112.5(TRPS1):​c.1088T>C​(p.Leu363Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TRPS1 NM_014112.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.25
• 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRPS1	NM_014112.5	c.1088T>C	p.Leu363Ser	missense_variant	Exon 4 of 7	ENST00000395715.8	NP_054831.2
TRPS1	NM_001282903.3	c.1067T>C	p.Leu356Ser	missense_variant	Exon 4 of 7		NP_001269832.1
TRPS1	NM_001282902.3	c.1061T>C	p.Leu354Ser	missense_variant	Exon 3 of 6		NP_001269831.1
TRPS1	NM_001330599.2	c.1049T>C	p.Leu350Ser	missense_variant	Exon 3 of 6		NP_001317528.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TRPS1	ENST00000395715.8	c.1088T>C	p.Leu363Ser	missense_variant	Exon 4 of 7	1	NM_014112.5	ENSP00000379065.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

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	0.19	D
BayesDel_noAF	Uncertain	0.040
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.34	T;.;T;.;.;T;.
Eigen	Uncertain	0.66
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D;D;.;D;D;D;D
M_CAP	Benign	0.049	D
MetaRNN	Uncertain	0.73	D;D;D;D;D;D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.97	L;.;L;.;.;.;.
PhyloP100		9.2
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	-1.4	.;N;N;N;N;D;.
REVEL	Uncertain	0.45
Sift	Pathogenic	0.0	.;D;D;D;D;D;.
Sift4G	Pathogenic	0.0	.;D;D;D;D;D;D
Polyphen		1.0	D;D;D;.;D;.;.
Vest4		0.83, 0.80, 0.93, 0.88, 0.95
MutPred		0.60		Loss of helix (P = 0.0104);.;Loss of helix (P = 0.0104);.;.;Loss of helix (P = 0.0104);.;
MVP		0.55
MPC		0.57
ClinPred		0.96	D
GERP RS		5.7
Varity_R		0.47
gMVP		0.90
Mutation Taster		=39/61	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: rs1554596397; hg19: chr8-116617108;