Variant 8-94838474-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_StrongBP6_ModerateBP7BS2

The NM_017864.4(INTS8):c.873A>G(p.Leu291Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.003 in 1,612,474 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.0020 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0031 ( 4 hom. )

Consequence

INTS8
NM_017864.4 synonymous

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:4

Conservation

PhyloP100: 1.17

Variant links:

Genes affected

INTS8 (HGNC:26048): (integrator complex subunit 8) This gene encodes a subunit of the Integrator complex which is involved in the cleavage of small nuclear RNAs U1 and U2 within the nucleus. The encoded protein associates with RNA polymerase II and is recruited to the U1 and U2 small nuclear RNA genes. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Nov 2012]

INTS8 links:

INTS8 (HGNC:):

INTS8 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -11 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.47).

BP6

Variant 8-94838474-A-G is Benign according to our data. Variant chr8-94838474-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 1285099.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr8-94838474-A-G is described in Lovd as [Likely_benign].

BP7

Synonymous conserved (PhyloP=1.17 with no splicing effect.

BS2

High Homozygotes in GnomAdExome4 at 4 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
INTS8	NM_017864.4 linkuse as main transcript	c.873A>G	p.Leu291Leu	synonymous_variant	8/27	ENST00000523731.6	NP_060334.2	Q75QN2-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
INTS8	ENST00000523731.6 linkuse as main transcript	c.873A>G	p.Leu291Leu	synonymous_variant	8/27	1	NM_017864.4	ENSP00000430338.1		Q75QN2-1

Frequencies

GnomAD3 genomes

AF:

0.00198

AC:

301

AN:

152198

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000700

Gnomad AMI

AF:

0.00329

Gnomad AMR

AF:

0.000851

Gnomad ASJ

AF:

0.00490

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00124

Gnomad FIN

AF:

0.00179

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00313

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00208

AC:

522

AN:

251208

Hom.:

AF XY:

0.00210

AC XY:

285

AN XY:

135780

show subpopulations

Gnomad AFR exome

AF:

0.000677

Gnomad AMR exome

AF:

0.000463

Gnomad ASJ exome

AF:

0.00477

Gnomad EAS exome

AF:

0.000163

Gnomad SAS exome

AF:

0.000981

Gnomad FIN exome

AF:

0.00287

Gnomad NFE exome

AF:

0.00305

Gnomad OTH exome

AF:

0.000816

GnomAD4 exome

AF:

0.00311

AC:

4537

AN:

1460158

Hom.:

Cov.:

AF XY:

0.00307

AC XY:

2227

AN XY:

726542

show subpopulations

Gnomad4 AFR exome

AF:

0.000299

Gnomad4 AMR exome

AF:

0.000447

Gnomad4 ASJ exome

AF:

0.00579

Gnomad4 EAS exome

AF:

0.00222

Gnomad4 SAS exome

AF:

0.00139

Gnomad4 FIN exome

AF:

0.00251

Gnomad4 NFE exome

AF:

0.00346

Gnomad4 OTH exome

AF:

0.00283

GnomAD4 genome

AF:

0.00197

AC:

300

AN:

152316

Hom.:

Cov.:

AF XY:

0.00184

AC XY:

137

AN XY:

74468

show subpopulations

Gnomad4 AFR

AF:

0.000698

Gnomad4 AMR

AF:

0.000850

Gnomad4 ASJ

AF:

0.00490

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00104

Gnomad4 FIN

AF:

0.00179

Gnomad4 NFE

AF:

0.00313

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.00300

Hom.:

Bravo

AF:

0.00220

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.00360

EpiControl

AF:

0.00297

ClinVar

Significance: Likely benign

Submissions summary: Benign:4

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:3

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

INTS8-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 25, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.47

CADD

Benign

6.6

DANN

Benign

0.66

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over