chr14-91968333-AT-A

Variant names:

• chr14-91968333-AT-A
• rs35251290
• NM_004239.4:c.*1339delA

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BS1_Supporting BS2

The NM_004239.4(TRIP11):​c.*1339delA variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0122 in 196,938 control chromosomes in the GnomAD database, including 44 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.013 (39 hom., cov: 31)
  • Exomes 𝑓: 0.011 (5 hom.)
• Consequence: TRIP11 NM_004239.4 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.00100
• Publications: 0 publications found

Genes affected

TRIP11 (HGNC:12305): (thyroid hormone receptor interactor 11) This gene was identified based on the interaction of its protein product with thyroid hormone receptor beta. This protein is associated with the Golgi apparatus. The N-terminal region of the protein binds Golgi membranes and the C-terminal region binds the minus ends of microtubules; thus, the protein is thought to play a role in assembly and maintenance of the Golgi ribbon structure around the centrosome. Mutations in this gene cause achondrogenesis type IA.[provided by RefSeq, Mar 2010]

TRIP11 Gene-Disease associations (from GenCC):

• achondrogenesis type IA

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, G2P, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), Orphanet
• TRIP11-related skeletal dysplasia

  Inheritance: AR Classification: DEFINITIVE Submitted by: Ambry Genetics, ClinGen

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0125 (1882/150328) while in subpopulation AFR AF = 0.0417 (1715/41094). AF 95% confidence interval is 0.0401. There are 39 homozygotes in GnomAd4. There are 883 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd4 at 39 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004239.4. 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
	TRIP11	NM_004239.4	MANE Select	c.*1339delA		3_prime_UTR	Exon 21 of 21	NP_004230.2	Q15643-1
	TRIP11	NM_001321851.1		c.*1339delA		3_prime_UTR	Exon 21 of 21	NP_001308780.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRIP11	ENST00000267622.8	TSL:1 MANE Select	c.*1339delA		3_prime_UTR	Exon 21 of 21	ENSP00000267622.4	Q15643-1
	TRIP11	ENST00000913145.1		c.*1339delA		3_prime_UTR	Exon 21 of 21	ENSP00000583204.1
	TRIP11	ENST00000876362.1		c.*1339delA		downstream_gene	N/A	ENSP00000546421.1

Frequencies

GnomAD3 genomes AF: 0.0125 AC: 1884 AN: 150218 Hom.: 39 Cov.: 31

Gnomad AFR AF: 0.0419

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00625

Gnomad ASJ AF: 0.000290

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.00695

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.000341

Gnomad OTH AF: 0.00777

GnomAD4 exome AF: 0.0111 AC: 518 AN: 46610 Hom.: 5 Cov.: 0 AF XY: 0.0117 AC XY: 252 AN XY: 21474

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0562 AC: 115 AN: 2046

American (AMR) AF: 0.0142 AC: 19 AN: 1342

Ashkenazi Jewish (ASJ) AF: 0.00810 AC: 24 AN: 2964

East Asian (EAS) AF: 0.00584 AC: 41 AN: 7018

South Asian (SAS) AF: 0.0148 AC: 6 AN: 406

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 30

Middle Eastern (MID) AF: 0.0143 AC: 4 AN: 280

European-Non Finnish (NFE) AF: 0.00893 AC: 256 AN: 28678

Other (OTH) AF: 0.0138 AC: 53 AN: 3846

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0125 AC: 1882 AN: 150328 Hom.: 39 Cov.: 31 AF XY: 0.0120 AC XY: 883 AN XY: 73396

African (AFR) AF: 0.0417 AC: 1715 AN: 41094

American (AMR) AF: 0.00624 AC: 94 AN: 15056

Ashkenazi Jewish (ASJ) AF: 0.000290 AC: 1 AN: 3444

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5148

South Asian (SAS) AF: 0.00654 AC: 31 AN: 4742

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10200

Middle Eastern (MID) AF: 0.00342 AC: 1 AN: 292

European-Non Finnish (NFE) AF: 0.000341 AC: 23 AN: 67362

Other (OTH) AF: 0.00770 AC: 16 AN: 2078

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Achondrogenesis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.0010
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: rs35251290; hg19: chr14-92434677;