rs193920828

Variant names:

• chr7-98978299-A-G
• rs193920828
• NM_001375524.1:c.8474A>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001375524.1(TRRAP):​c.8474A>G​(p.Gln2825Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: TRRAP NM_001375524.1 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 9.32
• Publications: 0 publications found

Genes affected

TRRAP (HGNC:12347): (transformation/transcription domain associated protein) This gene encodes a large multidomain protein of the phosphoinositide 3-kinase-related kinases (PIKK) family. The encoded protein is a common component of many histone acetyltransferase (HAT) complexes and plays a role in transcription and DNA repair by recruiting HAT complexes to chromatin. Deregulation of this gene may play a role in several types of cancer including glioblastoma multiforme. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Sep 2011]

TRRAP Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder with or without congenital anomalies

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• developmental delay with or without dysmorphic facies and autism

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Illumina, G2P
• autosomal dominant nonsyndromic hearing loss

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• hearing loss, autosomal dominant 75

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001375524.1. 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
	TRRAP	NM_001375524.1	MANE Select	c.8474A>G	p.Gln2825Arg	missense	Exon 57 of 73	NP_001362453.1	H0Y4W2
	TRRAP	NM_001244580.2		c.8453A>G	p.Gln2818Arg	missense	Exon 56 of 72	NP_001231509.1	Q9Y4A5-1
	TRRAP	NM_003496.4		c.8399A>G	p.Gln2800Arg	missense	Exon 55 of 71	NP_003487.1	Q9Y4A5-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRRAP	ENST00000456197.2	TSL:1 MANE Select	c.8474A>G	p.Gln2825Arg	missense	Exon 57 of 73	ENSP00000394645.2	H0Y4W2
	TRRAP	ENST00000359863.8	TSL:1	c.8453A>G	p.Gln2818Arg	missense	Exon 56 of 72	ENSP00000352925.4	Q9Y4A5-1
	TRRAP	ENST00000355540.7	TSL:1	c.8399A>G	p.Gln2800Arg	missense	Exon 55 of 71	ENSP00000347733.3	Q9Y4A5-2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	1	-	Prostate cancer (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Pathogenic	0.16	D
BayesDel_noAF	Uncertain	0.0
CADD	Uncertain	23
DANN	Benign	0.97
DEOGEN2	Benign	0.23	T
Eigen	Uncertain	0.25
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.0029	T
MetaRNN	Uncertain	0.62	D
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	-0.90	N
PhyloP100		9.3
PrimateAI	Pathogenic	0.80	T
PROVEAN	Benign	-0.37	N
REVEL	Uncertain	0.32
Sift	Benign	0.53	T
Sift4G	Benign	0.82	T
Polyphen		0.0070	B
Vest4		0.87
MutPred		0.40		Gain of MoRF binding (P = 0.0551)
MVP		0.75
MPC		0.67
ClinPred		0.77	D
GERP RS		6.1
Varity_R		0.37
gMVP		0.55
Mutation Taster		=55/45	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: rs193920828; hg19: chr7-98575922; COSMIC: COSV62855400; COSMIC: COSV62855400;