1-1312115-G-C

Variant names:

• chr1-1312115-G-C
• rs755005813
• NM_017871.6:c.1640C>G

Variant summary

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

The NM_017871.6(INTS11):​c.1640C>G​(p.Pro547Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000014 in 1,424,658 control chromosomes in the GnomAD database, with no homozygous occurrence. 12/21 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. P547T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 25)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: INTS11 NM_017871.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.12

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 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
INTS11	NM_017871.6	c.1640C>G	p.Pro547Arg	missense_variant	Exon 16 of 17	ENST00000435064.6	NP_060341.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
INTS11	ENST00000435064.6	c.1640C>G	p.Pro547Arg	missense_variant	Exon 16 of 17	1	NM_017871.6	ENSP00000413493.2

Frequencies

GnomAD3 genomes Cov.: 25

GnomAD3 exomes AF: 0.0000197 AC: 4 AN: 203216 Hom.: 0 AF XY: 0.0000367 AC XY: 4 AN XY: 109024

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000242

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000140 AC: 2 AN: 1424658 Hom.: 0 Cov.: 35 AF XY: 0.00000284 AC XY: 2 AN XY: 704208

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000512

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 25

Bravo AF: 0.00000378

ExAC AF: 0.0000253 AC: 3

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 12, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1640C>G (p.P547R) alteration is located in exon 16 (coding exon 16) of the CPSF3L gene. This alteration results from a C to G substitution at nucleotide position 1640, causing the proline (P) at amino acid position 547 to be replaced by an arginine (R). 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	0.26
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.11
CADD	Benign	23
DANN	Benign	0.92
DEOGEN2	Benign	0.022	.;.;.;T;T;T;.;.;.
Eigen	Benign	-0.024
Eigen_PC	Benign	0.033
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.97	D;D;D;D;D;D;D;D;D
M_CAP	Benign	0.028	D
MetaRNN	Uncertain	0.65	D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	1.7	.;.;.;.;L;.;.;.;.
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-0.48	N;N;.;.;N;N;.;N;N
REVEL	Benign	0.25
Sift	Benign	0.28	T;T;.;.;T;T;.;T;T
Sift4G	Benign	0.26	T;T;T;D;T;T;T;T;T
Polyphen		0.16, 0.28, 0.53, 0.25	.;.;.;.;B;B;.;P;B
Vest4		0.73
MutPred		0.44		.;.;.;.;Gain of catalytic residue at P547 (P = 0.0098);.;.;.;.;
MVP		0.84
MPC		0.032
ClinPred		0.21	T
GERP RS		4.0
Varity_R		0.50
gMVP		0.36

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs755005813; hg19: chr1-1247495;