17-46030372-C-CA

Position:

• chr17-46030372-C-CA

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BS1_Supporting BS2

The NM_015443.4(KANSL1):​c.*1103dupT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0214 in 148,080 control chromosomes in the GnomAD database, including 47 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.021 (47 hom., cov: 30)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: KANSL1 NM_015443.4 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.50

Genes affected

KANSL1 (HGNC:24565): (KAT8 regulatory NSL complex subunit 1) This gene encodes a nuclear protein that is a subunit of two protein complexes involved with histone acetylation, the MLL1 complex and the NSL1 complex. The encoded protein has been implicated in a variety of cellular processes including enhancer regulation, cell proliferation, and mitosis. Mutations in this gene are associated with Koolen-de Vries Syndrome. [provided by RefSeq, May 2022]

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0214 (3174/148080) while in subpopulation NFE AF= 0.0306 (2047/66926). AF 95% confidence interval is 0.0295. There are 47 homozygotes in gnomad4. There are 1606 alleles in male gnomad4 subpopulation. Median coverage is 30. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd4 at 3174 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KANSL1	NM_015443.4	c.*1103dupT		3_prime_UTR_variant	15/15	ENST00000432791.7	NP_056258.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KANSL1	ENST00000432791	c.*1103dupT		3_prime_UTR_variant	15/15	1	NM_015443.4	ENSP00000387393.3

Frequencies

GnomAD3 genomes AF: 0.0215 AC: 3176 AN: 147980 Hom.: 47 Cov.: 30

Gnomad AFR AF: 0.00423

Gnomad AMI AF: 0.0993

Gnomad AMR AF: 0.0171

Gnomad ASJ AF: 0.0277

Gnomad EAS AF: 0.000197

Gnomad SAS AF: 0.00879

Gnomad FIN AF: 0.0457

Gnomad MID AF: 0.00321

Gnomad NFE AF: 0.0306

Gnomad OTH AF: 0.0188

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 10 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 10

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0214 AC: 3174 AN: 148080 Hom.: 47 Cov.: 30 AF XY: 0.0223 AC XY: 1606 AN XY: 72064

Gnomad4 AFR AF: 0.00419

Gnomad4 AMR AF: 0.0171

Gnomad4 ASJ AF: 0.0277

Gnomad4 EAS AF: 0.000198

Gnomad4 SAS AF: 0.00882

Gnomad4 FIN AF: 0.0457

Gnomad4 NFE AF: 0.0306

Gnomad4 OTH AF: 0.0186

Bravo AF: 0.0181

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Syndromic intellectual disability Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs142756815; hg19: chr17-44107738;