7-1471181-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_001080453.3(INTS1):​c.6299G>A​(p.Arg2100His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000657 in 1,584,000 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 34)
Exomes 𝑓: 0.000069 ( 0 hom. )

Consequence

INTS1
NM_001080453.3 missense

Scores

10
8
1

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.51
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 Uncertain_significance. Variant got 3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.822

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
INTS1NM_001080453.3 linkuse as main transcriptc.6299G>A p.Arg2100His missense_variant 46/48 ENST00000404767.8
INTS1XM_011515260.2 linkuse as main transcriptc.6329G>A p.Arg2110His missense_variant 46/48

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
INTS1ENST00000404767.8 linkuse as main transcriptc.6299G>A p.Arg2100His missense_variant 46/485 NM_001080453.3 P1
INTS1ENST00000483196.1 linkuse as main transcriptc.338G>A p.Arg113His missense_variant 4/45
INTS1ENST00000479671.1 linkuse as main transcriptn.235G>A non_coding_transcript_exon_variant 2/22
INTS1ENST00000493446.1 linkuse as main transcriptn.283G>A non_coding_transcript_exon_variant 4/63

Frequencies

GnomAD3 genomes
AF:
0.0000329
AC:
5
AN:
152206
Hom.:
0
Cov.:
34
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000654
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000207
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000294
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
0.0000691
AC:
99
AN:
1431794
Hom.:
0
Cov.:
31
AF XY:
0.0000719
AC XY:
51
AN XY:
709244
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000245
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000263
Gnomad4 SAS exome
AF:
0.0000490
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000828
Gnomad4 OTH exome
AF:
0.0000337
GnomAD4 genome
AF:
0.0000329
AC:
5
AN:
152206
Hom.:
0
Cov.:
34
AF XY:
0.0000538
AC XY:
4
AN XY:
74354
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.0000654
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000207
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000294
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000574
Hom.:
0
Bravo
AF:
0.0000189
ExAC
AF:
0.00000849
AC:
1

ClinVar

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

Submissions by phenotype

Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsMay 20, 2024The c.6299G>A (p.R2100H) alteration is located in exon 46 (coding exon 45) of the INTS1 gene. This alteration results from a G to A substitution at nucleotide position 6299, causing the arginine (R) at amino acid position 2100 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.86
BayesDel_addAF
Pathogenic
0.22
D
BayesDel_noAF
Uncertain
0.080
CADD
Pathogenic
30
DANN
Pathogenic
1.0
DEOGEN2
Uncertain
0.75
D;.
Eigen
Pathogenic
0.79
Eigen_PC
Pathogenic
0.77
FATHMM_MKL
Pathogenic
1.0
D
LIST_S2
Uncertain
0.96
D;D
M_CAP
Uncertain
0.15
D
MetaRNN
Pathogenic
0.82
D;D
MetaSVM
Uncertain
0.24
D
MutationAssessor
Uncertain
2.5
M;.
MutationTaster
Benign
1.0
D;D
PrimateAI
Uncertain
0.60
T
PROVEAN
Uncertain
-4.3
D;D
REVEL
Pathogenic
0.69
Sift
Pathogenic
0.0
D;D
Sift4G
Pathogenic
0.0
D;.
Polyphen
1.0
D;.
Vest4
0.79
MVP
0.86
ClinPred
1.0
D
GERP RS
5.4
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.85
gMVP
0.81

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.

Other links and lift over

dbSNP: rs751110317; hg19: chr7-1510817; COSMIC: COSV67178817; COSMIC: COSV67178817; API