NM_004239.4:c.4812T>C

Variant names:

• chr14-91999320-A-G
• rs17127837
• NM_004239.4:c.4812T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_004239.4(TRIP11):​c.4812T>C​(p.Asp1604Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00428 in 1,613,904 control chromosomes in the GnomAD database, including 261 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.023 (138 hom., cov: 32)
  • Exomes 𝑓: 0.0024 (123 hom.)
• Consequence: TRIP11 NM_004239.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.0720
• Publications: 2 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.58).
• BP6: Variant 14-91999320-A-G is Benign according to our data. Variant chr14-91999320-A-G is described in ClinVar as Benign. ClinVar VariationId is 314935.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.072 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0761 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.4812T>C	p.Asp1604Asp	synonymous	Exon 13 of 21	NP_004230.2	Q15643-1
	TRIP11	NM_001321851.1		c.4809T>C	p.Asp1603Asp	synonymous	Exon 13 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.4812T>C	p.Asp1604Asp	synonymous	Exon 13 of 21	ENSP00000267622.4	Q15643-1
	TRIP11	ENST00000554357.5	TSL:1	c.3957T>C	p.Asp1319Asp	synonymous	Exon 7 of 15	ENSP00000451032.1	H0YJ97
	TRIP11	ENST00000913145.1		c.4809T>C	p.Asp1603Asp	synonymous	Exon 13 of 21	ENSP00000583204.1

Frequencies

GnomAD3 genomes AF: 0.0226 AC: 3433 AN: 152148 Hom.: 137 Cov.: 32

Gnomad AFR AF: 0.0784

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00812

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000368

Gnomad OTH AF: 0.0163

GnomAD2 exomes AF: 0.00582 AC: 1460 AN: 250894 AF XY: 0.00410

Gnomad AFR exome AF: 0.0781

Gnomad AMR exome AF: 0.00373

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000344

Gnomad OTH exome AF: 0.00327

GnomAD4 exome AF: 0.00237 AC: 3461 AN: 1461638 Hom.: 123 Cov.: 32 AF XY: 0.00206 AC XY: 1497 AN XY: 727120

African (AFR) AF: 0.0802 AC: 2685 AN: 33466

American (AMR) AF: 0.00411 AC: 184 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39656

South Asian (SAS) AF: 0.000174 AC: 15 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53366

Middle Eastern (MID) AF: 0.00382 AC: 22 AN: 5758

European-Non Finnish (NFE) AF: 0.000194 AC: 216 AN: 1111912

Other (OTH) AF: 0.00561 AC: 339 AN: 60382

GnomAD4 genome AF: 0.0226 AC: 3442 AN: 152266 Hom.: 138 Cov.: 32 AF XY: 0.0217 AC XY: 1615 AN XY: 74446

African (AFR) AF: 0.0784 AC: 3255 AN: 41542

American (AMR) AF: 0.00811 AC: 124 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.000368 AC: 25 AN: 68016

Other (OTH) AF: 0.0161 AC: 34 AN: 2114

Alfa AF: 0.00905 Hom.: 73

Bravo AF: 0.0260

Asia WGS AF: 0.00549 AC: 19 AN: 3476

EpiCase AF: 0.000164

EpiControl AF: 0.000296

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Achondrogenesis, type IA (2)
-	-	2	not provided (2)
-	-	1	Connective tissue disorder (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
CADD	Benign	0.67
DANN	Benign	0.50
PhyloP100		0.072
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs17127837; hg19: chr14-92465664; COSMIC: COSV50915820;