Genetic Variant INTS6:p.Thr749Ala (chr13-51369170-T-C) – ACMG Classification: Benign (-16 pts)

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_012141.3(INTS6):c.2245A>G(p.Thr749Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000657 in 1,613,914 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0035 ( 5 hom., cov: 32)

Exomes 𝑓: 0.00036 ( 5 hom. )

Consequence

INTS6
NM_012141.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.713

Publications

0 publications found

Variant links:

Genes affected

INTS6 (HGNC:14879): (integrator complex subunit 6) DEAD box proteins, characterized by the conserved motif Asp-Glu-Ala-Asp (DEAD), are putative RNA helicases. The protein encoded by this gene is a DEAD box protein that is part of a complex that interacts with the C-terminus of RNA polymerase II and is involved in 3' end processing of snRNAs. In addition, this gene is a candidate tumor suppressor and is located in the critical region of loss of heterozygosity (LOH). Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Apr 2015]

INTS6 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0049500763).

BP6

Variant 13-51369170-T-C is Benign according to our data. Variant chr13-51369170-T-C is described in ClinVar as [Benign]. Clinvar id is 787108.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Homozygotes in GnomAd4 at 5 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
INTS6	NM_012141.3 link	c.2245A>G	p.Thr749Ala	missense_variant	Exon 16 of 18	ENST00000311234.9	NP_036273.1	Q9UL03-1A0A024RDU0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
INTS6	ENST00000311234.9 link	c.2245A>G	p.Thr749Ala	missense_variant	Exon 16 of 18	1	NM_012141.3	ENSP00000310260.4		Q9UL03-1

Frequencies

GnomAD3 genomes

AF:

0.00348

AC:

530

AN:

152174

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0122

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00118

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.00143

GnomAD2 exomes

AF:

0.00104

AC:

261

AN:

251216

AF XY:

0.000854

show subpopulations

Gnomad AFR exome

AF:

0.0135

Gnomad AMR exome

AF:

0.000869

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000704

Gnomad OTH exome

AF:

0.000490

GnomAD4 exome

AF:

0.000363

AC:

530

AN:

1461622

Hom.:

Cov.:

AF XY:

0.000293

AC XY:

213

AN XY:

727110

show subpopulations

African (AFR)

AF:

0.0119

AC:

399

AN:

33460

American (AMR)

AF:

0.00112

AC:

AN:

44704

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26118

East Asian (EAS)

AF:

0.00

AC:

AN:

39674

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53414

Middle Eastern (MID)

AF:

0.000347

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.0000108

AC:

AN:

1111848

Other (OTH)

AF:

0.00109

AC:

AN:

60382

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

118

148

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00348

AC:

530

AN:

152292

Hom.:

Cov.:

AF XY:

0.00342

AC XY:

255

AN XY:

74478

show subpopulations

African (AFR)

AF:

0.0121

AC:

504

AN:

41562

American (AMR)

AF:

0.00118

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000735

AC:

AN:

68020

Other (OTH)

AF:

0.00142

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

110

137

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00131

Hom.:

Bravo

AF:

0.00397

ESP6500AA

AF:

0.0123

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00107

AC:

130

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Apr 04, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.055

BayesDel_addAF

Benign

-0.55

BayesDel_noAF

Benign

-0.56

CADD

Benign

(source)

DANN

Benign

0.78

DEOGEN2

Benign

0.13

.;T;T;T

Eigen

Benign

-0.37

Eigen_PC

Benign

-0.12

FATHMM_MKL

Uncertain

0.83

LIST_S2

Benign

0.56

T;T;T;T

MetaRNN

Benign

0.0050

T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.1

.;L;.;.

PhyloP100

0.71

PrimateAI

Benign

0.31

PROVEAN

Benign

-0.47

N;N;N;N

REVEL

Benign

0.063

Sift

Benign

0.64

T;T;T;T

Sift4G

Benign

0.81

T;T;T;T

Polyphen

0.0

.;B;.;.

Vest4

0.15

MVP

0.29

MPC

0.31

ClinPred

0.0080

GERP RS

5.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.041

gMVP

0.21

Mutation Taster

=98/2

polymorphism

(source)

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

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13-51369170-T-C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over