7-98881209-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP2 PP3

The NM_001375524.1(TRRAP):c.59A>G(p.Lys20Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: TRRAP NM_001375524.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.14

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, TRRAP
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TRRAP	NM_001375524.1	c.59A>G	p.Lys20Arg	missense_variant	2/73	ENST00000456197.2
TRRAP	NM_001244580.2	c.59A>G	p.Lys20Arg	missense_variant	2/72
TRRAP	NM_003496.4	c.59A>G	p.Lys20Arg	missense_variant	2/71

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TRRAP	ENST00000456197.2	c.59A>G	p.Lys20Arg	missense_variant	2/73	1	NM_001375524.1	P2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 31

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

Centogene AG - the Rare Disease Company

May 14, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.068	T
BayesDel_noAF	Benign	-0.34
Cadd	Pathogenic	30
Dann	Uncertain	0.99
DEOGEN2	Benign	0.092	T;T;.;.;.
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D;D;D;D;.
M_CAP	Benign	0.0026	T
MetaRNN	Benign	0.41	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	-1.4	N;N;N;.;N
REVEL	Benign	0.17
Sift	Benign	0.14	T;T;T;.;T
Sift4G	Pathogenic	0.0	D;T;T;T;T
Polyphen		0.96, 0.97	.;P;D;.;.
Vest4		0.64, 0.61, 0.64, 0.61
MutPred		0.31		Loss of methylation at K20 (P = 0.0262);Loss of methylation at K20 (P = 0.0262);Loss of methylation at K20 (P = 0.0262);Loss of methylation at K20 (P = 0.0262);Loss of methylation at K20 (P = 0.0262);
MVP		0.56
MPC		0.74
ClinPred		0.77	D
GERP RS		6.1
Varity_R		0.34
gMVP		0.58

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.56		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.56		Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr7-98478832;