chr4-105682891-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_020395.4(INTS12):​c.1231G>A​(p.Gly411Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000031 in 1,613,982 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

INTS12
NM_020395.4 missense

Scores

1
4
14

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.56
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]
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.35962743).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
INTS12NM_020395.4 linkuse as main transcriptc.1231G>A p.Gly411Arg missense_variant 8/8 ENST00000340139.10

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
INTS12ENST00000340139.10 linkuse as main transcriptc.1231G>A p.Gly411Arg missense_variant 8/81 NM_020395.4 P1
INTS12ENST00000451321.6 linkuse as main transcriptc.1231G>A p.Gly411Arg missense_variant 7/71 P1
INTS12ENST00000394735.5 linkuse as main transcriptc.1231G>A p.Gly411Arg missense_variant 8/85 P1
ARHGEF38ENST00000503289.1 linkuse as main transcriptn.308-31C>T intron_variant, non_coding_transcript_variant 3

Frequencies

GnomAD3 genomes
AF:
0.0000263
AC:
4
AN:
152178
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000965
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:
0.00
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461804
Hom.:
0
Cov.:
31
AF XY:
0.00000138
AC XY:
1
AN XY:
727202
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:
8.99e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000263
AC:
4
AN:
152178
Hom.:
0
Cov.:
32
AF XY:
0.0000269
AC XY:
2
AN XY:
74334
show subpopulations
Gnomad4 AFR
AF:
0.0000965
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:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.00000378

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 submitterclinical testingAmbry GeneticsFeb 15, 2023The c.1231G>A (p.G411R) alteration is located in exon 8 (coding exon 6) of the INTS12 gene. This alteration results from a G to A substitution at nucleotide position 1231, causing the glycine (G) at amino acid position 411 to be replaced by an arginine (R). 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
Uncertain
0.34
BayesDel_addAF
Benign
-0.022
T
BayesDel_noAF
Benign
-0.27
CADD
Benign
21
DANN
Uncertain
1.0
DEOGEN2
Benign
0.046
T;T;T;T
Eigen
Benign
0.19
Eigen_PC
Benign
0.13
FATHMM_MKL
Pathogenic
0.97
D
LIST_S2
Benign
0.74
.;.;T;T
M_CAP
Benign
0.048
D
MetaRNN
Benign
0.36
T;T;T;T
MetaSVM
Benign
-0.68
T
MutationAssessor
Benign
0.90
L;L;L;.
MutationTaster
Benign
1.0
D;D;D
PrimateAI
Uncertain
0.68
T
PROVEAN
Benign
-0.98
N;N;N;.
REVEL
Benign
0.18
Sift
Uncertain
0.0020
D;D;D;.
Sift4G
Benign
0.54
T;T;T;T
Polyphen
0.99
D;D;D;.
Vest4
0.54
MutPred
0.21
Gain of methylation at G411 (P = 0.027);Gain of methylation at G411 (P = 0.027);Gain of methylation at G411 (P = 0.027);Gain of methylation at G411 (P = 0.027);
MVP
0.32
MPC
0.85
ClinPred
0.73
D
GERP RS
5.2
Varity_R
0.17
gMVP
0.26

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: rs1362102658; hg19: chr4-106604048; API