7-98881209-A-G

Position:

• chr7-98881209-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 in gene, where missense usually causes diseases (based on misZ statistic), TRRAP. . Gene score misZ 8.173 (greater than the threshold 3.09). Trascript score misZ 10.503 (greater than threshold 3.09). GenCC has associacion of gene with autosomal dominant nonsyndromic hearing loss, developmental delay with or without dysmorphic facies and autism, hearing loss, autosomal dominant 75, complex neurodevelopmental disorder with or without congenital anomalies.
• 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
MutationAssessor	Benign	1.4	.;L;L;.;.
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;