7-1470874-G-T

Position:

• chr7-1470874-G-T

Variant summary

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

The NM_001080453.3(INTS1):​c.6429C>A​(p.Asn2143Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000347 in 1,442,088 control chromosomes in the GnomAD database, with no homozygous occurrence. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000035 (0 hom.)
• Consequence: INTS1 NM_001080453.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.21

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
INTS1	NM_001080453.3	c.6429C>A	p.Asn2143Lys	missense_variant	47/48	ENST00000404767.8	NP_001073922.2
INTS1	XM_011515260.2	c.6459C>A	p.Asn2153Lys	missense_variant	47/48		XP_011513562.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
INTS1	ENST00000404767.8	c.6429C>A	p.Asn2143Lys	missense_variant	47/48	5	NM_001080453.3	ENSP00000385722	P1
INTS1	ENST00000493446.1	n.413C>A		non_coding_transcript_exon_variant	5/6	3

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.00000347 AC: 5 AN: 1442088 Hom.: 0 Cov.: 31 AF XY: 0.00000559 AC XY: 4 AN XY: 715738

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: 0.00000272

Gnomad4 OTH exome AF: 0.0000335

GnomAD4 genome Cov.: 34

ExAC AF: 0.0000167 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 13, 2021

The c.6429C>A (p.N2143K) alteration is located in exon 47 (coding exon 46) of the INTS1 gene. This alteration results from a C to A substitution at nucleotide position 6429, causing the asparagine (N) at amino acid position 2143 to be replaced by a lysine (K). 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	Pathogenic	0.64
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	21
DANN	Benign	0.64
DEOGEN2	Benign	0.15	T
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.095
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.028	D
MetaRNN	Uncertain	0.45	T
MetaSVM	Benign	-0.72	T
MutationAssessor	Uncertain	2.4	M
MutationTaster	Benign	0.99	D;D
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.19
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0080	B
Vest4		0.70
MutPred		0.41		Loss of catalytic residue at N2143 (P = 0.0121);
MVP		0.55
ClinPred		0.18	T
GERP RS		5.6
Varity_R		0.35
gMVP		0.56

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: rs755849785; hg19: chr7-1510510;