Variant 4-105682944-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_020395.4(INTS12):c.1178T>C(p.Leu393Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000558 in 1,614,000 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

INTS12
NM_020395.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.96

Variant links:

Genes affected

INTS12 (HGNC:25067): (integrator complex subunit 12) INTS12 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]

INTS12 links:

ARHGEF38 (HGNC:25968): (Rho guanine nucleotide exchange factor 38) Predicted to enable guanyl-nucleotide exchange factor activity. Predicted to be involved in regulation of catalytic activity. Predicted to be located in cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ARHGEF38 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.039909154).

BS2

High AC in GnomAdExome4 at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
INTS12	NM_020395.4 linkuse as main transcript	c.1178T>C	p.Leu393Ser	missense_variant	8/8	ENST00000340139.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
INTS12	ENST00000340139.10 linkuse as main transcript	c.1178T>C	p.Leu393Ser	missense_variant	8/8	1	NM_020395.4	P1
INTS12	ENST00000451321.6 linkuse as main transcript	c.1178T>C	p.Leu393Ser	missense_variant	7/7	1		P1
INTS12	ENST00000394735.5 linkuse as main transcript	c.1178T>C	p.Leu393Ser	missense_variant	8/8	5		P1
ARHGEF38	ENST00000503289.1 linkuse as main transcript	n.330A>G		non_coding_transcript_exon_variant	4/5	3

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152172

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000796

AC:

AN:

251412

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135874

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:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000479

AC:

AN:

1461828

Hom.:

Cov.:

AF XY:

0.00000688

AC XY:

AN XY:

727210

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:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000270

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152172

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74348

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000579

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 01, 2024

The c.1178T>C (p.L393S) alteration is located in exon 8 (coding exon 6) of the INTS12 gene. This alteration results from a T to C substitution at nucleotide position 1178, causing the leucine (L) at amino acid position 393 to be replaced by a serine (S). 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

Benign

0.076

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.61

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.017

T;T;T;T

Eigen

Benign

-0.47

Eigen_PC

Benign

-0.30

FATHMM_MKL

Benign

0.21

LIST_S2

Benign

0.61

.;.;T;T

M_CAP

Benign

0.0031

MetaRNN

Benign

0.040

T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.14

N;N;N;.

MutationTaster

Benign

0.95

N;N;N

PrimateAI

Benign

0.40

PROVEAN

Benign

0.35

N;N;N;.

REVEL

Benign

0.089

Sift

Benign

0.59

T;T;T;.

Sift4G

Benign

0.63

T;T;T;T

Polyphen

0.0010

B;B;B;.

Vest4

0.059

MVP

0.12

MPC

0.38

ClinPred

0.13

GERP RS

4.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.029

gMVP

0.076

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