chr4-105695649-A-G

Position:

• chr4-105695649-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_020395.4(INTS12):​c.176T>C​(p.Ile59Thr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: INTS12 NM_020395.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.92

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.11598465).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
INTS12	NM_020395.4	c.176T>C	p.Ile59Thr	missense_variant	4/8	ENST00000340139.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
INTS12	ENST00000340139.10	c.176T>C	p.Ile59Thr	missense_variant	4/8	1	NM_020395.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 15, 2023

The c.176T>C (p.I59T) alteration is located in exon 4 (coding exon 2) of the INTS12 gene. This alteration results from a T to C substitution at nucleotide position 176, causing the isoleucine (I) at amino acid position 59 to be replaced by a threonine (T). 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	0.17
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	21
DANN	Benign	0.97
DEOGEN2	Benign	0.014	T;T;T;T;.;.;T;T
Eigen	Benign	-0.17
Eigen_PC	Benign	0.058
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.84	.;.;T;T;T;T;T;T
M_CAP	Benign	0.0050	T
MetaRNN	Benign	0.12	T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.5	L;L;L;.;.;.;.;.
MutationTaster	Benign	0.57	N;N;N
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	0.11	N;N;N;.;N;N;N;N
REVEL	Benign	0.067
Sift	Benign	0.22	T;T;T;.;T;T;D;D
Sift4G	Benign	0.24	T;T;T;T;.;.;.;.
Polyphen		0.32	B;B;B;.;.;.;.;.
Vest4		0.20
MutPred		0.14		Gain of phosphorylation at I59 (P = 0.0394);Gain of phosphorylation at I59 (P = 0.0394);Gain of phosphorylation at I59 (P = 0.0394);Gain of phosphorylation at I59 (P = 0.0394);Gain of phosphorylation at I59 (P = 0.0394);Gain of phosphorylation at I59 (P = 0.0394);Gain of phosphorylation at I59 (P = 0.0394);Gain of phosphorylation at I59 (P = 0.0394);
MVP		0.22
MPC		0.33
ClinPred		0.49	T
GERP RS		5.6
Varity_R		0.056
gMVP		0.12

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

Other links and lift over

dbSNP: rs1731836269; hg19: chr4-106616806;