1-1312098-C-T

Variant names:

• chr1-1312098-C-T
• rs932999699
• NM_017871.6:c.1657G>A

Variant summary

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

The NM_017871.6(INTS11):​c.1657G>A​(p.Val553Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000444 in 1,577,566 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: INTS11 NM_017871.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.20

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.1657G>A	p.Val553Met	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.1657G>A	p.Val553Met	missense_variant	Exon 16 of 17	1	NM_017871.6	ENSP00000413493.2

Frequencies

GnomAD3 genomes AF: 0.0000331 AC: 5 AN: 150906 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000122

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000140 AC: 2 AN: 1426660 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 705828

Gnomad4 AFR exome AF: 0.0000300

Gnomad4 AMR exome AF: 0.0000249

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000331 AC: 5 AN: 150906 Hom.: 0 Cov.: 32 AF XY: 0.0000136 AC XY: 1 AN XY: 73588

Gnomad4 AFR AF: 0.000122

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000264

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 30, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1657G>A (p.V553M) alteration is located in exon 16 (coding exon 16) of the CPSF3L gene. This alteration results from a G to A substitution at nucleotide position 1657, causing the valine (V) at amino acid position 553 to be replaced by a methionine (M). 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	Uncertain	0.41
BayesDel_addAF	Uncertain	0.033	T
BayesDel_noAF	Benign	-0.19
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.031	.;.;.;T;T;T;.;.;.
Eigen	Benign	0.055
Eigen_PC	Benign	-0.0028
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.98	D;D;D;D;D;D;D;D;D
M_CAP	Benign	0.068	D
MetaRNN	Uncertain	0.71	D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.79	T
MutationAssessor	Benign	1.9	.;.;.;.;L;.;.;.;.
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-0.83	N;N;.;.;N;N;.;N;N
REVEL	Benign	0.20
Sift	Uncertain	0.0040	D;D;.;.;D;D;.;D;D
Sift4G	Uncertain	0.010	D;D;D;D;D;D;D;D;D
Polyphen		0.91, 0.95, 0.32	.;.;.;.;P;P;.;P;B
Vest4		0.86
MutPred		0.53		.;.;.;.;Gain of disorder (P = 0.156);.;.;.;.;
MVP		0.62
MPC		0.19
ClinPred		0.41	T
GERP RS		3.1
Varity_R		0.34
gMVP		0.51

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		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: rs932999699; hg19: chr1-1247478;