rs74615166

Variant names:

• chr15-64433291-T-C
• rs74615166
• NM_016213.5:c.1575+7660T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_016213.5(TRIP4):​c.1575+7660T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0157 in 152,250 control chromosomes in the GnomAD database, including 25 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.016 (25 hom., cov: 32)
• Consequence: TRIP4 NM_016213.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.328
• Publications: 16 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0157 (2397/152250) while in subpopulation SAS AF = 0.0247 (119/4820). AF 95% confidence interval is 0.0211. There are 25 homozygotes in GnomAd4. There are 1208 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 25 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRIP4	NM_016213.5	c.1575+7660T>C		intron_variant	Intron 11 of 12	ENST00000261884.8	NP_057297.2
TRIP4	NM_001321924.2	c.885+7660T>C		intron_variant	Intron 11 of 12		NP_001308853.1
TRIP4	NR_135855.2	n.1476+7660T>C		intron_variant	Intron 10 of 11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TRIP4	ENST00000261884.8	c.1575+7660T>C		intron_variant	Intron 11 of 12	1	NM_016213.5	ENSP00000261884.3
TRIP4	ENST00000558162.1	c.132+7660T>C		intron_variant	Intron 2 of 3	3		ENSP00000452764.1
TRIP4	ENST00000560475.1	c.111-11715T>C		intron_variant	Intron 1 of 2	3		ENSP00000454558.1

Frequencies

GnomAD3 genomes AF: 0.0158 AC: 2403 AN: 152132 Hom.: 26 Cov.: 32

Gnomad AFR AF: 0.00393

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.0158

Gnomad ASJ AF: 0.00259

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0249

Gnomad FIN AF: 0.0302

Gnomad MID AF: 0.0478

Gnomad NFE AF: 0.0218

Gnomad OTH AF: 0.0225

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

GnomAD4 genome AF: 0.0157 AC: 2397 AN: 152250 Hom.: 25 Cov.: 32 AF XY: 0.0162 AC XY: 1208 AN XY: 74442

African (AFR) AF: 0.00392 AC: 163 AN: 41560

American (AMR) AF: 0.0158 AC: 241 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00259 AC: 9 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5174

South Asian (SAS) AF: 0.0247 AC: 119 AN: 4820

European-Finnish (FIN) AF: 0.0302 AC: 321 AN: 10614

Middle Eastern (MID) AF: 0.0342 AC: 10 AN: 292

European-Non Finnish (NFE) AF: 0.0218 AC: 1482 AN: 68012

Other (OTH) AF: 0.0227 AC: 48 AN: 2112

Alfa AF: 0.0176 Hom.: 11

Bravo AF: 0.0140

Asia WGS AF: 0.00924 AC: 32 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.77
DANN	Benign	0.61
PhyloP100		-0.33
Mutation Taster		=100/0	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: rs74615166; hg19: chr15-64725490;