Variant 7-98882016-A-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2PP2BP4

The NM_001375524.1(TRRAP):c.142A>T(p.Asn48Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,459,216 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

TRRAP
NM_001375524.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.90

Variant links:

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 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 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.

BP4

Computational evidence support a benign effect (MetaRNN=0.40822083).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
TRRAP	NM_001375524.1 linkuse as main transcript	c.142A>T	p.Asn48Tyr	missense_variant	3/73	ENST00000456197.2
TRRAP	NM_001244580.2 linkuse as main transcript	c.142A>T	p.Asn48Tyr	missense_variant	3/72
TRRAP	NM_003496.4 linkuse as main transcript	c.142A>T	p.Asn48Tyr	missense_variant	3/71

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TRRAP	ENST00000456197.2 linkuse as main transcript	c.142A>T	p.Asn48Tyr	missense_variant	3/73	1	NM_001375524.1	P2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1459216

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

725812

show subpopulations

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:

9.00e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jan 16, 2023

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.56

BayesDel_addAF

Uncertain

0.062

BayesDel_noAF

Benign

-0.15

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.22

T;D;.;.;.

Eigen

Benign

0.066

Eigen_PC

Uncertain

0.23

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.94

D;D;D;D;.

M_CAP

Benign

0.0047

MetaRNN

Benign

0.41

T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.5

.;M;M;.;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Pathogenic

0.90

PROVEAN

Pathogenic

-6.3

D;D;D;.;D

REVEL

Benign

0.22

Sift

Uncertain

0.0040

D;D;D;.;D

Sift4G

Pathogenic

0.0

D;D;D;D;D

Polyphen

0.34, 0.47

.;B;P;.;.

Vest4

0.71, 0.76, 0.71, 0.73

MutPred

0.27

Loss of disorder (P = 0.031);Loss of disorder (P = 0.031);Loss of disorder (P = 0.031);Loss of disorder (P = 0.031);Loss of disorder (P = 0.031);

MVP

0.51

MPC

1.9

ClinPred

0.98

GERP RS

5.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.30

gMVP

0.94

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over