15-64409735-GA-CC

Variant names:

• chr15-64409735-GA-CC
• NM_016213.5:c.950_951delGAinsCC
• TRIP4 p.Arg317Pro

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM5 PP3

The NM_016213.5(TRIP4):​c.950_951delGAinsCC​(p.Arg317Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. 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. R317Q) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TRIP4 NM_016213.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.74
• 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: G2P, Labcorp Genetics (formerly Invitae), Genomics England PanelApp

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr15-64409735-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 253117.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRIP4	NM_016213.5	MANE Select	c.950_951delGAinsCC	p.Arg317Pro	missense	N/A	NP_057297.2
	TRIP4	NM_001321924.2		c.260_261delGAinsCC	p.Arg87Pro	missense	N/A	NP_001308853.1
	TRIP4	NR_135855.2		n.978_979delGAinsCC		non_coding_transcript_exon	Exon 7 of 12

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRIP4	ENST00000261884.8	TSL:1 MANE Select	c.950_951delGAinsCC	p.Arg317Pro	missense	N/A	ENSP00000261884.3	Q15650
	TRIP4	ENST00000949916.1		c.950_951delGAinsCC	p.Arg317Pro	missense	N/A	ENSP00000619975.1
	TRIP4	ENST00000935230.1		c.941_942delGAinsCC	p.Arg314Pro	missense	N/A	ENSP00000605289.1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.7

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr15-64701934;