rs750300935

Variant names:

• chr1-1312271-CGT-C
• rs750300935
• NM_017871.6:c.1560_1561delAC

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_017871.6(INTS11):​c.1560_1561delAC​(p.Arg521GlnfsTer44) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000213 in 1,549,234 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000020 (0 hom.)
• Consequence: INTS11 NM_017871.6 frameshift
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.29

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 Pathogenic. Variant got 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-1312271-CGT-C is Pathogenic according to our data. Variant chr1-1312271-CGT-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3376978.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-1312271-CGT-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
INTS11	NM_017871.6	c.1560_1561delAC	p.Arg521GlnfsTer44	frameshift_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.1560_1561delAC	p.Arg521GlnfsTer44	frameshift_variant	Exon 15 of 17	1	NM_017871.6	ENSP00000413493.2

Frequencies

GnomAD3 genomes AF: 0.0000330 AC: 5 AN: 151642 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

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: 0.000382

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000193 AC: 3 AN: 155148 Hom.: 0 AF XY: 0.0000244 AC XY: 2 AN XY: 82068

Gnomad AFR exome AF: 0.000113

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000131

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000200 AC: 28 AN: 1397592 Hom.: 0 AF XY: 0.0000174 AC XY: 12 AN XY: 689314

Gnomad4 AFR exome AF: 0.0000314

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000126

Gnomad4 FIN exome AF: 0.000167

Gnomad4 NFE exome AF: 0.0000148

Gnomad4 OTH exome AF: 0.0000345

GnomAD4 genome AF: 0.0000330 AC: 5 AN: 151642 Hom.: 0 Cov.: 33 AF XY: 0.0000676 AC XY: 5 AN XY: 74000

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000382

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000113

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Neurodevelopmental disorder with motor and language delay, ocular defects, and brain abnormalities Pathogenic:1

Oct 08, 2024

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as likely pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Neurodevelopmental disorder with motor and language delay, ocular defects, and brain abnormalities (MIM#620428). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0205 - Variant is predicted to result in a truncated protein (premature termination codon is NOT located at least 54 nucleotides upstream of the final exon-exon junction) with less than 1/3 of the protein sequence affected. (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (4 heterozygotes, 0 homozygotes). (SP) 0600 - Variant is located in the affected C-terminal domain (DECIPHER). (I) 0704 - Another protein truncating variant comparable to the one identified in this case has limited previous evidence for pathogenicity. The comparable p.(Val557Aspfs*14) variant was identified in a compound heterozygous individual with severe global developmental delay, mild to moderate intellectual disability, language delay and moderate cerebellar atrophy (PMID:37054711). (SP) 0803 - This variant has limited previous evidence of pathogenicity in unrelated individuals. Two siblings from a single family were reported as compound heterozygous for this variant. Both of these individuals had severe global developmental delay, intellectual disability, language delay, brain abnormalities on MRI, hypotonia and seizures (PMID:37054711) . (SP) 1007 - No published functional evidence has been identified for this variant. (I) 1205 - This variant has been shown to be maternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Computational scores

Source: dbNSFP v4.3

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

LitVar

Other links and lift over

dbSNP: rs750300935; hg19: chr1-1247651;