X-135546391-AT-ATT

Variant names:

• chrX-135546391-A-AT
• rs782242788
• NM_001351601.3:c.359dupT

Variant summary

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

The NM_001351601.3(INTS6L):​c.359dupT​(p.Leu120PhefsTer37) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000773 in 1,034,549 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000077 (0 hom. 0 hem.)
• Consequence: INTS6L NM_001351601.3 frameshift
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.67

Genes affected

INTS6L (HGNC:27334): (integrator complex subunit 6 like) Predicted to be involved in snRNA 3'-end processing. Predicted to be part of integrator complex. [provided by Alliance of Genome Resources, Apr 2022]

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 rank	MANE	Protein	UniProt
INTS6L	NM_001351601.3	c.359dupT	p.Leu120PhefsTer37	frameshift_variant	Exon 4 of 18	ENST00000639893.2	NP_001338530.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
INTS6L	ENST00000639893.2	c.359dupT	p.Leu120PhefsTer37	frameshift_variant	Exon 4 of 18	5	NM_001351601.3	ENSP00000491427.1
INTS6L	ENST00000370752.4	c.359dupT	p.Leu120PhefsTer37	frameshift_variant	Exon 4 of 17	1		ENSP00000359788.4
INTS6L	ENST00000493637.6	n.359dupT		non_coding_transcript_exon_variant	Exon 4 of 16	1
INTS6L	ENST00000481908.5	n.693dupT		non_coding_transcript_exon_variant	Exon 4 of 16	2

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 0.00000773 AC: 8 AN: 1034549 Hom.: 0 Cov.: 24 AF XY: 0.00 AC XY: 0 AN XY: 326115

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000428

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000353

Gnomad4 SAS exome AF: 0.0000227

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000616

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 23

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.20		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.20		Position offset: -11

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs782242788; hg19: chrX-134680316;