chr7-1470922-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_ModeratePM2PP5_Moderate

The NM_001080453.3(INTS1):ā€‹c.6381C>Gā€‹(p.Tyr2127*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (ā˜…).

Frequency

Genomes: not found (cov: 33)
Exomes š‘“: 7.0e-7 ( 0 hom. )
Failed GnomAD Quality Control

Consequence

INTS1
NM_001080453.3 stop_gained

Scores

4
2
1

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 2.97
Variant links:
Genes affected
INTS1 (HGNC:24555): (integrator complex subunit 1) INTS1 is a subunit of the Integrator complex, which associates with the C-terminal domain of RNA polymerase II large subunit (POLR2A; MIM 180660) and mediates 3-prime end processing of small nuclear RNAs U1 (RNU1; MIM 180680) and U2 (RNU2; MIM 180690) (Baillat et al., 2005 [PubMed 16239144]).[supplied by OMIM, Mar 2008]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0292 CDS is truncated, and there are 1 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 7-1470922-G-C is Pathogenic according to our data. Variant chr7-1470922-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 643062.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
INTS1NM_001080453.3 linkc.6381C>G p.Tyr2127* stop_gained 47/48 ENST00000404767.8 NP_001073922.2 Q8N201
INTS1XM_011515260.2 linkc.6411C>G p.Tyr2137* stop_gained 47/48 XP_011513562.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
INTS1ENST00000404767.8 linkc.6381C>G p.Tyr2127* stop_gained 47/485 NM_001080453.3 ENSP00000385722.3 Q8N201
INTS1ENST00000493446.1 linkn.365C>G non_coding_transcript_exon_variant 5/63

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD3 exomes
AF:
0.00000517
AC:
1
AN:
193370
Hom.:
0
AF XY:
0.00000956
AC XY:
1
AN XY:
104598
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000398
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
Data not reliable, filtered out with message: AS_VQSR
AF:
7.00e-7
AC:
1
AN:
1428686
Hom.:
0
Cov.:
31
AF XY:
0.00000141
AC XY:
1
AN XY:
707786
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:
0.0000122
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not provided Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpDec 19, 2019This sequence change creates a premature translational stop signal (p.Tyr2127*) in the INTS1 gene. It is expected to result in an absent or disrupted protein product. For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in INTS1 are known to be pathogenic (PMID: 28542170, 30622326). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. This variant has not been reported in the literature in individuals with INTS1-related conditions. ClinVar contains an entry for this variant (Variation ID: 643062). This variant is not present in population databases (ExAC no frequency). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.62
D
BayesDel_noAF
Pathogenic
0.65
CADD
Pathogenic
54
DANN
Uncertain
1.0
Eigen
Pathogenic
0.77
Eigen_PC
Uncertain
0.64
FATHMM_MKL
Pathogenic
0.98
D
Vest4
0.22
GERP RS
5.6

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.76
Details are displayed if max score is > 0.2
DS_AG_spliceai
0.76
Position offset: -1

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.

Other links and lift over

dbSNP: rs1432925039; hg19: chr7-1510558; API