X-135546391-A-AT

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. 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
• Publications: 5 publications found

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

Our verdict: Uncertain_significance. The variant received 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
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

GnomAD2 exomes AF: 0.0000378 AC: 5 AN: 132442 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000137

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000105

Gnomad FIN exome AF: 0.0000696

Gnomad NFE exome AF: 0.0000155

Gnomad OTH exome AF: 0.00

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

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 23048

American (AMR) AF: 0.0000428 AC: 1 AN: 23390

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17390

East Asian (EAS) AF: 0.0000353 AC: 1 AN: 28352

South Asian (SAS) AF: 0.0000227 AC: 1 AN: 44015

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39173

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3758

European-Non Finnish (NFE) AF: 0.00000616 AC: 5 AN: 812226

Other (OTH) AF: 0.00 AC: 0 AN: 43197

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 23

Alfa AF: 0.00 Hom.: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.7

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

Other links and lift over

dbSNP: rs782242788; hg19: chrX-134680316; COSMIC: COSV66083573;