Genetic Variant INTS1:p.Leu2149Val (chr7-1470858-G-C) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001080453.3(INTS1):c.6445C>G(p.Leu2149Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000626 in 1,438,442 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L2149F) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000063 ( 0 hom. )

Consequence

INTS1
NM_001080453.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.85

Publications

1 publications found

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]

INTS1 Gene-Disease associations (from GenCC):

neurodevelopmental disorder with cataracts, poor growth, and dysmorphic facies
Inheritance: AR Classification: STRONG, MODERATE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics

INTS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001080453.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	INTS1	NM_001080453.3	MANE Select	c.6445C>G	p.Leu2149Val	missense	Exon 47 of 48	NP_001073922.2	Q8N201

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
INTS1	ENST00000404767.8	TSL:5 MANE Select	c.6445C>G	p.Leu2149Val	missense	Exon 47 of 48	ENSP00000385722.3	Q8N201
INTS1	ENST00000951930.1		c.6688C>G	p.Leu2230Val	missense	Exon 48 of 49	ENSP00000621989.1
INTS1	ENST00000916004.1		c.6532C>G	p.Leu2178Val	missense	Exon 47 of 48	ENSP00000586063.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000475

AC:

AN:

210676

AF XY:

0.00

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000187

GnomAD4 exome

AF:

0.00000626

AC:

AN:

1438442

Hom.:

Cov.:

AF XY:

0.00000841

AC XY:

AN XY:

713600

show subpopulations

African (AFR)

AF:

0.0000912

AC:

AN:

32892

American (AMR)

AF:

0.00

AC:

AN:

41528

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25764

East Asian (EAS)

AF:

0.00

AC:

AN:

38250

South Asian (SAS)

AF:

0.00

AC:

AN:

82872

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50336

Middle Eastern (MID)

AF:

0.000174

AC:

AN:

5748

European-Non Finnish (NFE)

AF:

0.00000363

AC:

AN:

1101494

Other (OTH)

AF:

0.0000168

AC:

AN:

59558

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000282

Hom.:

Bravo

AF:

0.00000378

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Uncertain

0.040

BayesDel_noAF

Benign

-0.18

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.14

Eigen

Uncertain

0.21

Eigen_PC

Uncertain

0.27

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.91

M_CAP

Benign

0.034

MetaRNN

Uncertain

0.48

MetaSVM

Benign

-0.65

MutationAssessor

Benign

1.9

PhyloP100

7.8

PrimateAI

Uncertain

0.61

PROVEAN

Benign

-0.83

REVEL

Benign

0.24

Sift

Benign

0.13

Sift4G

Benign

0.20

Polyphen

0.57

Vest4

0.52

MutPred

0.28

Loss of helix (P = 0.079)

MVP

0.58

ClinPred

0.57

GERP RS

5.4

Varity_R

0.32

gMVP

0.33

Mutation Taster

=74/26

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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over