chr7-1470876-T-G

Position:

• chr7-1470876-T-G

Variant summary

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

The NM_001080453.3(INTS1):​c.6427A>C​(p.Asn2143His) variant causes a missense change. The variant allele was found at a frequency of 0.0000132 in 1,442,398 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. 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. N2143K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.000013 (0 hom.)
• Consequence: INTS1 NM_001080453.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.19

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]

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=0.22703949).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
INTS1	NM_001080453.3	c.6427A>C	p.Asn2143His	missense_variant	47/48	ENST00000404767.8
INTS1	XM_011515260.2	c.6457A>C	p.Asn2153His	missense_variant	47/48

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
INTS1	ENST00000404767.8	c.6427A>C	p.Asn2143His	missense_variant	47/48	5	NM_001080453.3	P1
INTS1	ENST00000493446.1	n.411A>C		non_coding_transcript_exon_variant	5/6	3

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD3 exomes AF: 0.0000277 AC: 6 AN: 216484 Hom.: 0 AF XY: 0.00000848 AC XY: 1 AN XY: 117900

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: 0.000208

Gnomad NFE exome AF: 0.0000104

Gnomad OTH exome AF: 0.000184

GnomAD4 exome AF: 0.0000132 AC: 19 AN: 1442398 Hom.: 0 Cov.: 31 AF XY: 0.00000419 AC XY: 3 AN XY: 715926

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: 0.0000988

Gnomad4 NFE exome AF: 0.0000118

Gnomad4 OTH exome AF: 0.0000167

GnomAD4 genome Cov.: 34

Alfa AF: 0.0000468 Hom.: 0

ExAC AF: 0.0000250 AC: 3

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.073	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.18	T
Eigen	Benign	0.029
Eigen_PC	Benign	0.15
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.040	D
MetaRNN	Benign	0.23	T
MetaSVM	Benign	-0.69	T
MutationAssessor	Uncertain	2.4	M
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.24
Sift	Benign	0.097	T
Sift4G	Benign	0.12	T
Polyphen		0.048	B
Vest4		0.54
MutPred		0.40		Loss of catalytic residue at N2143 (P = 0.0087);
MVP		0.58
ClinPred		0.14	T
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.34
gMVP		0.54

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: rs779893699; hg19: chr7-1510512;