chr15-64409735-G-C

Variant names:

• chr15-64409735-G-C
• rs200549601
• NM_016213.5:c.950G>C

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PM5 PP3

The NM_016213.5(TRIP4):​c.950G>C​(p.Arg317Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,880 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R317Q) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• 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: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, G2P

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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: MetaRNN computational evidence supports a deleterious effect, 0.812

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.950G>C	p.Arg317Pro	missense	Exon 7 of 13	NP_057297.2
	TRIP4	NM_001321924.2		c.260G>C	p.Arg87Pro	missense	Exon 7 of 13	NP_001308853.1
	TRIP4	NR_135855.2		n.978G>C		non_coding_transcript_exon	Exon 7 of 12

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRIP4	ENST00000261884.8	TSL:1 MANE Select	c.950G>C	p.Arg317Pro	missense	Exon 7 of 13	ENSP00000261884.3
	TRIP4	ENST00000560475.1	TSL:3	c.17G>C	p.Arg6Pro	missense	Exon 1 of 3	ENSP00000454558.1
	TRIP4	ENST00000559565.5	TSL:3	n.694G>C		non_coding_transcript_exon	Exon 6 of 6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461880 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727236

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86246

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1112012

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.41
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.44	T
Eigen	Pathogenic	0.94
Eigen_PC	Pathogenic	0.91
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.037	D
MetaRNN	Pathogenic	0.81	D
MetaSVM	Uncertain	0.086	D
MutationAssessor	Pathogenic	3.1	M
PhyloP100		7.7
PrimateAI	Uncertain	0.67	T
PROVEAN	Pathogenic	-4.9	D
REVEL	Pathogenic	0.66
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.010	D
Polyphen		1.0	D
Vest4		0.81
MutPred		0.39		Loss of MoRF binding (P = 0.003)
MVP		0.42
MPC		0.48
ClinPred		1.0	D
GERP RS		5.7
PromoterAI		-0.097	Neutral
Varity_R		0.91
gMVP		0.67
Mutation Taster		=20/80	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs200549601; hg19: chr15-64701934;