chr15-64395476-C-T

Variant names:

• chr15-64395476-C-T
• rs1555408852
• NM_016213.5:c.350C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_016213.5(TRIP4):​c.350C>T​(p.Ala117Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: TRIP4 NM_016213.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.66
• Publications: 0 publications found

Genes affected

TRIP4 (HGNC:12310): (thyroid hormone receptor interactor 4) This gene encodes a subunit of the tetrameric nuclear activating signal cointegrator 1 (ASC-1) complex, which associates with transcriptional coactivators, nuclear receptors and basal transcription factors to facilitate nuclear receptors-mediated transcription. This protein is localized in the nucleus and contains an E1A-type zinc finger domain, which mediates interaction with transcriptional coactivators and ligand-bound nuclear receptors, such as thyroid hormone receptor and retinoid X receptor alpha, but not glucocorticoid receptor. Mutations in this gene are associated with spinal muscular atrophy with congenital bone fractures-1 (SMABF1). [provided by RefSeq, Apr 2016]

TRIP4 Gene-Disease associations (from GenCC):

• prenatal-onset spinal muscular atrophy with congenital bone fractures

  Inheritance: AR Classification: STRONG Submitted by: Genomics England PanelApp
• spinal muscular atrophy with congenital bone fractures 1

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, G2P

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08148983).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016213.5. 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
	TRIP4	NM_016213.5	MANE Select	c.350C>T	p.Ala117Val	missense	Exon 3 of 13	NP_057297.2
	TRIP4	NM_001321924.2		c.-341C>T		5_prime_UTR	Exon 3 of 13	NP_001308853.1
	TRIP4	NR_135855.2		n.378C>T		non_coding_transcript_exon	Exon 3 of 12

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRIP4	ENST00000261884.8	TSL:1 MANE Select	c.350C>T	p.Ala117Val	missense	Exon 3 of 13	ENSP00000261884.3
	TRIP4	ENST00000949916.1		c.350C>T	p.Ala117Val	missense	Exon 3 of 14	ENSP00000619975.1
	TRIP4	ENST00000935230.1		c.341C>T	p.Ala114Val	missense	Exon 3 of 13	ENSP00000605289.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.033	T
Eigen	Benign	-0.14
Eigen_PC	Benign	0.020
FATHMM_MKL	Benign	0.56	D
LIST_S2	Benign	0.74	T
M_CAP	Benign	0.0026	T
MetaRNN	Benign	0.081	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	1.3	L
PhyloP100		1.7
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.062
Sift	Benign	0.37	T
Sift4G	Benign	0.39	T
Polyphen		0.028	B
Vest4		0.14
MutPred		0.19		Gain of sheet (P = 0.0125)
MVP		0.46
MPC		0.068
ClinPred		0.61	D
GERP RS		5.3
Varity_R		0.071
gMVP		0.14
Mutation Taster		=84/16	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: rs1555408852; hg19: chr15-64687675;