Genetic Variant TRIP4:p.Arg278Gly (chr15-64409617-C-G) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

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

The NM_016213.5(TRIP4):c.832C>G(p.Arg278Gly) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,560 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

TRIP4
NM_016213.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.78

Publications

0 publications found

Variant links:

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

TRIP4 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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
TRIP4	NM_016213.5 link	c.832C>G	p.Arg278Gly	missense_variant	Exon 7 of 13	ENST00000261884.8	NP_057297.2	Q15650
TRIP4	NM_001321924.2 link	c.142C>G	p.Arg48Gly	missense_variant	Exon 7 of 13		NP_001308853.1	Q15650
TRIP4	NR_135855.2 link	n.860C>G		non_coding_transcript_exon_variant	Exon 7 of 12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TRIP4	ENST00000261884.8 link	c.832C>G	p.Arg278Gly	missense_variant	Exon 7 of 13	1	NM_016213.5	ENSP00000261884.3		Q15650

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461560

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727082

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33462

American (AMR)

AF:

0.00

AC:

AN:

44660

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26122

East Asian (EAS)

AF:

0.00

AC:

AN:

39690

South Asian (SAS)

AF:

0.00

AC:

AN:

86188

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53410

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5724

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111918

Other (OTH)

AF:

0.00

AC:

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.52

BayesDel_addAF

Pathogenic

0.36

BayesDel_noAF

Pathogenic

0.28

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.43

Eigen

Pathogenic

0.72

Eigen_PC

Pathogenic

0.70

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.98

M_CAP

Benign

0.017

MetaRNN

Uncertain

0.72

MetaSVM

Uncertain

-0.088

MutationAssessor

Pathogenic

3.1

PhyloP100

3.8

PrimateAI

Uncertain

0.74

PROVEAN

Pathogenic

-5.1

REVEL

Uncertain

0.58

Sift

Uncertain

0.010

Sift4G

Uncertain

0.014

Polyphen

1.0

Vest4

0.92

MutPred

0.47

Gain of loop (P = 0.0195);

MVP

0.27

MPC

0.39

ClinPred

0.99

GERP RS

5.7

PromoterAI

0.011

Neutral

(source)

Varity_R

0.64

gMVP

0.34

Mutation Taster

=36/64

disease causing

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over