7-1470586-GGCCTCCATAT-AGGCTCACATCACG

Position:

• chr7-1470586-GGCCTCCATAT-AGGCTCACATCACG

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_001080453.3(INTS1):​c.6554_6564delATATGGAGGCCinsCGTGATGTGAGCCT​(p.His2185_Ala2188delinsProTerCysGluPro) variant causes a stop gained, missense, conservative inframe insertion change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: INTS1 NM_001080453.3 stop_gained, missense, conservative_inframe_insertion
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.07

Genes affected

INTS1 (HGNC:24555): (integrator complex subunit 1) INTS1 is a subunit of the Integrator complex, which associates with the C-terminal domain of RNA polymerase II large subunit (POLR2A; MIM 180660) and mediates 3-prime end processing of small nuclear RNAs U1 (RNU1; MIM 180680) and U2 (RNU2; MIM 180690) (Baillat et al., 2005 [PubMed 16239144]).[supplied by OMIM, Mar 2008]

ACMG classification

Verdict is Pathogenic. Variant got 10 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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
INTS1	NM_001080453.3	c.6554_6564delATATGGAGGCCinsCGTGATGTGAGCCT	p.His2185_Ala2188delinsProTerCysGluPro	stop_gained, missense_variant, conservative_inframe_insertion		ENST00000404767.8	NP_001073922.2
INTS1	XM_011515260.2	c.6584_6594delATATGGAGGCCinsCGTGATGTGAGCCT	p.His2195_Ala2198delinsProTerCysGluPro	stop_gained, missense_variant, conservative_inframe_insertion			XP_011513562.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
INTS1	ENST00000404767.8	c.6554_6564delATATGGAGGCCinsCGTGATGTGAGCCT	p.His2185_Ala2188delinsProTerCysGluPro	stop_gained, missense_variant, conservative_inframe_insertion		5	NM_001080453.3	ENSP00000385722.3
INTS1	ENST00000493446.1	n.557_567delATATGGAGGCCinsCGTGATGTGAGCCT		non_coding_transcript_exon_variant	6/6	3

Frequencies

GnomAD3 genomes Cov.: 33

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 25, 2022

The c.6554_6564del11insCGTGATGTGAGCCT (p.H2185_A2188delinsP*) alteration, located in exon 48 (coding exon 47) of the INTS1 gene, consists of an in-frame deletion of 11 and insertion of 14 nucleotides from position 6554 to 6564, resulting in the insertion of a premature termination codon. This alteration occurs at the 3' terminus of the INTS1 gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 0.1% of the protein. The exact functional effect of this alteration is unknown. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Splicing

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: chr7-1510222;