1-153728773-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_023015.5(INTS3):c.139G>A(p.Glu47Lys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 30)
• Consequence: INTS3 NM_023015.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.82

Genes affected

INTS3 (HGNC:26153): (integrator complex subunit 3) The protein encoded by this gene can form a complex with human single-strand DNA binding proteins 1 or 2 (hSSB1 and hSSB2) and other proteins to mediate genome stability and the DNA damage response. The encoded protein is also part of a multiprotein complex that interacts with the C-terminal domain of RNA polymerase II large subunit to help regulate processing of U1 and U2 small nuclear RNAs. [provided by RefSeq, May 2016]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, INTS3

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
INTS3	NM_023015.5	c.139G>A	p.Glu47Lys	missense_variant	1/30	ENST00000318967.7
INTS3	NM_001324475.2	c.139G>A	p.Glu47Lys	missense_variant	2/31

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
INTS3	ENST00000318967.7	c.139G>A	p.Glu47Lys	missense_variant	1/30	1	NM_023015.5	P1
INTS3	ENST00000435409.6	c.139G>A	p.Glu47Lys	missense_variant	2/31	2		P1
INTS3	ENST00000481797.5	n.291G>A		non_coding_transcript_exon_variant	1/29	2

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 30

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

Aug 22, 2023

The c.139G>A (p.E47K) alteration is located in exon 1 (coding exon 1) of the INTS3 gene. This alteration results from a G to A substitution at nucleotide position 139, causing the glutamic acid (E) at amino acid position 47 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
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.060
Cadd	Pathogenic	27
Dann	Pathogenic	1.0
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Uncertain	0.79	D
M_CAP	Benign	0.0079	T
MetaRNN	Uncertain	0.48	T;T
MetaSVM	Benign	-0.61	T
MutationAssessor	Uncertain	2.4	M;M
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.84	D
PROVEAN	Uncertain	-3.2	D;D
REVEL	Benign	0.24
Sift	Uncertain	0.011	D;D
Sift4G	Uncertain	0.028	D;D
Polyphen		0.59	P;P
Vest4		0.60
MutPred		0.29		Gain of ubiquitination at E47 (P = 0.0042);Gain of ubiquitination at E47 (P = 0.0042);
MVP		0.59
MPC		0.71
ClinPred		0.99	D
GERP RS		5.1
gMVP		0.39

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-153701249;