7-98881978-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_001375524.1(TRRAP):c.104A>G(p.Asp35Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 1,459,378 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: TRRAP NM_001375524.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.53

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, TRRAP

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TRRAP	NM_001375524.1	c.104A>G	p.Asp35Gly	missense_variant	3/73	ENST00000456197.2
TRRAP	NM_001244580.2	c.104A>G	p.Asp35Gly	missense_variant	3/72
TRRAP	NM_003496.4	c.104A>G	p.Asp35Gly	missense_variant	3/71

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TRRAP	ENST00000456197.2	c.104A>G	p.Asp35Gly	missense_variant	3/73	1	NM_001375524.1	P2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1459378 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 725780

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Developmental delay with or without dysmorphic facies and autism Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Institute of Human Genetics, University of Leipzig Medical Center

Jan 01, 2019

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.68
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.090
Cadd	Pathogenic	27
Dann	Uncertain	0.99
DEOGEN2	Benign	0.22	T;D;.;.;.
Eigen	Pathogenic	0.69
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.96	D;D;D;D;.
M_CAP	Benign	0.012	T
MetaRNN	Uncertain	0.63	D;D;D;D;D
MetaSVM	Benign	-0.95	T
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-6.2	D;D;D;.;D
REVEL	Uncertain	0.41
Sift	Pathogenic	0.0	D;D;D;.;D
Sift4G	Pathogenic	0.0	D;D;D;D;D
Polyphen		0.99, 1.0	.;D;D;.;.
Vest4		0.70, 0.69, 0.66, 0.68
MutPred		0.25		Gain of ubiquitination at K40 (P = 0.1051);Gain of ubiquitination at K40 (P = 0.1051);Gain of ubiquitination at K40 (P = 0.1051);Gain of ubiquitination at K40 (P = 0.1051);Gain of ubiquitination at K40 (P = 0.1051);
MVP		0.68
MPC		1.8
ClinPred		1.0	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.58
gMVP		0.95

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

Publications

LitVar

Other links and lift over

dbSNP: rs1795461647; hg19: chr7-98479601;