14-91968333-ATTT-ATTTT

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_004239.4(TRIP11):​c.*1339dupA variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0209 in 197,954 control chromosomes in the GnomAD database, including 133 homozygotes. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.024 (131 hom., cov: 31)
  • Exomes 𝑓: 0.012 (2 hom.)
• Consequence: TRIP11 NM_004239.4 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B: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: Benign. The variant received -10 ACMG points.

• BP6: Variant 14-91968333-A-AT is Benign according to our data. Variant chr14-91968333-A-AT is described in ClinVar as Likely_benign. ClinVar VariationId is 314897.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0714 is higher than 0.05.

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.*1339dupA		3_prime_UTR	Exon 21 of 21	NP_004230.2	Q15643-1
	TRIP11	NM_001321851.1		c.*1339dupA		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.*1339dupA		3_prime_UTR	Exon 21 of 21	ENSP00000267622.4	Q15643-1
	TRIP11	ENST00000913145.1		c.*1339dupA		3_prime_UTR	Exon 21 of 21	ENSP00000583204.1
	TRIP11	ENST00000876362.1		c.*1339dupA		downstream_gene	N/A	ENSP00000546421.1

Frequencies

GnomAD3 genomes AF: 0.0237 AC: 3557 AN: 150254 Hom.: 128 Cov.: 31

Gnomad AFR AF: 0.0732

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0105

Gnomad ASJ AF: 0.000290

Gnomad EAS AF: 0.0233

Gnomad SAS AF: 0.0381

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000816

Gnomad OTH AF: 0.0194

GnomAD4 exome AF: 0.0115 AC: 549 AN: 47590 Hom.: 2 Cov.: 0 AF XY: 0.0111 AC XY: 244 AN XY: 21960

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

African (AFR) AF: 0.0678 AC: 140 AN: 2064

American (AMR) AF: 0.00729 AC: 10 AN: 1372

Ashkenazi Jewish (ASJ) AF: 0.00500 AC: 15 AN: 3002

East Asian (EAS) AF: 0.0138 AC: 99 AN: 7182

South Asian (SAS) AF: 0.0476 AC: 20 AN: 420

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 32

Middle Eastern (MID) AF: 0.0107 AC: 3 AN: 280

European-Non Finnish (NFE) AF: 0.00658 AC: 193 AN: 29320

Other (OTH) AF: 0.0176 AC: 69 AN: 3918

⚠️ 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: 0.0239 AC: 3588 AN: 150364 Hom.: 131 Cov.: 31 AF XY: 0.0238 AC XY: 1746 AN XY: 73418

African (AFR) AF: 0.0736 AC: 3024 AN: 41088

American (AMR) AF: 0.0105 AC: 158 AN: 15060

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

East Asian (EAS) AF: 0.0233 AC: 120 AN: 5148

South Asian (SAS) AF: 0.0377 AC: 179 AN: 4742

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10222

Middle Eastern (MID) AF: 0.0171 AC: 5 AN: 292

European-Non Finnish (NFE) AF: 0.000816 AC: 55 AN: 67378

Other (OTH) AF: 0.0221 AC: 46 AN: 2078

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Likely benign

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 (auto)

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;