1-1312308-G-C

Variant names:

• chr1-1312308-G-C
• rs949448745
• NM_017871.6:c.1525C>G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_017871.6(INTS11):​c.1525C>G​(p.Leu509Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000136 in 1,399,328 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: 33)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: INTS11 NM_017871.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.53

Genes affected

INTS11 (HGNC:26052): (integrator complex subunit 11) The Integrator complex contains at least 12 subunits and associates with the C-terminal domain of RNA polymerase II large subunit (POLR2A; MIM 180660) and mediates the 3-prime end processing of small nuclear RNAs U1 (RNU1; MIM 180680) and U2 (RNU2; MIM 180690). INTS11, or CPSF3L, is the catalytic subunit of the Integrator complex (Baillat et al., 2005 [PubMed 16239144]).[supplied by OMIM, Mar 2008]

ACMG classification

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=0.3936054).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
INTS11	NM_017871.6	c.1525C>G	p.Leu509Val	missense_variant	Exon 15 of 17	ENST00000435064.6	NP_060341.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
INTS11	ENST00000435064.6	c.1525C>G	p.Leu509Val	missense_variant	Exon 15 of 17	1	NM_017871.6	ENSP00000413493.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.0000136 AC: 19 AN: 1399328 Hom.: 0 Cov.: 36 AF XY: 0.0000116 AC XY: 8 AN XY: 690334

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: 0.0000167

Gnomad4 OTH exome AF: 0.0000172

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 06, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1525C>G (p.L509V) alteration is located in exon 15 (coding exon 15) of the CPSF3L gene. This alteration results from a C to G substitution at nucleotide position 1525, causing the leucine (L) at amino acid position 509 to be replaced by a valine (V). 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	0.23
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Benign	-0.090
CADD	Benign	20
DANN	Benign	0.96
DEOGEN2	Benign	0.012	.;.;.;T;T;T;.;.;.
Eigen	Benign	-0.095
Eigen_PC	Benign	0.080
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.96	D;D;D;D;D;D;D;D;D
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.39	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	.;.;.;.;L;.;.;.;.
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-0.49	N;N;.;.;N;N;.;N;N
REVEL	Benign	0.16
Sift	Benign	0.61	T;T;.;.;T;T;.;T;T
Sift4G	Benign	0.83	T;T;T;T;T;T;T;T;T
Polyphen		0.019, 0.015, 0.032	.;.;.;.;B;B;.;B;B
Vest4		0.66
MutPred		0.43		.;.;.;.;Loss of helix (P = 0.1299);.;.;.;.;
MVP		0.57
MPC		0.033
ClinPred		0.29	T
GERP RS		4.7
Varity_R		0.21
gMVP		0.45

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs949448745; hg19: chr1-1247688;