chr1-1311922-G-C

Variant names:

• chr1-1311922-G-C
• NM_017871.6:c.1740C>G

Variant summary

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

The NM_017871.6(INTS11):​c.1740C>G​(p.Asp580Glu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000701 in 1,425,924 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. D580D) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: INTS11 NM_017871.6 missense, splice_region
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0270

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]

PUSL1 (HGNC:26914): (pseudouridine synthase like 1) Predicted to enable pseudouridine synthase activity. Predicted to be involved in tRNA pseudouridine synthesis. Located in mitochondrion. [provided by Alliance of Genome Resources, Apr 2022]

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.1740C>G	p.Asp580Glu	missense_variant, splice_region_variant	Exon 17 of 17	ENST00000435064.6	NP_060341.2
PUSL1	NM_153339.3	c.*543G>C		downstream_gene_variant		ENST00000379031.10	NP_699170.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
INTS11	ENST00000435064.6	c.1740C>G	p.Asp580Glu	missense_variant, splice_region_variant	Exon 17 of 17	1	NM_017871.6	ENSP00000413493.2
PUSL1	ENST00000379031.10	c.*543G>C		downstream_gene_variant		1	NM_153339.3	ENSP00000368318.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.01e-7 AC: 1 AN: 1425924 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 705100

Gnomad4 AFR exome AF: 0.0000312

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.60
BayesDel_addAF	Benign	-0.081	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	0.011
DANN	Benign	0.96
DEOGEN2	Benign	0.055	.;.;.;T;T;T;.;.;.
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.5
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.91	D;D;D;D;D;D;D;D;D
M_CAP	Uncertain	0.15	D
MetaRNN	Benign	0.25	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.59	T
MutationAssessor	Benign	1.8	.;.;.;.;L;.;.;.;.
PrimateAI	Pathogenic	0.80	T
PROVEAN	Benign	-1.6	N;N;.;.;N;N;.;N;N
REVEL	Uncertain	0.31
Sift	Benign	0.056	T;T;.;.;T;D;.;T;T
Sift4G	Benign	0.12	T;T;T;D;T;T;T;T;T
Polyphen		0.71, 0.96, 0.98, 0.89	.;.;.;.;P;D;.;D;P
Vest4		0.36
MutPred		0.59		.;.;.;.;Gain of disorder (P = 0.0789);.;.;.;.;
MVP		0.26
MPC		0.19
ClinPred		0.78	D
GERP RS		-6.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.37
gMVP		0.42

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.31		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.31		Position offset: -1

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: chr1-1247302;