17-46030522-G-C

Position:

• chr17-46030522-G-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_015443.4(KANSL1):​c.*954C>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00379 in 150,736 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0038 (0 hom., cov: 31)
  • Exomes 𝑓: 0.015 (0 hom.)
• Consequence: KANSL1 NM_015443.4 3_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 0.844

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 Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 17-46030522-G-C is Benign according to our data. Variant chr17-46030522-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 323748.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00379 (571/150668) while in subpopulation NFE AF= 0.00588 (399/67820). AF 95% confidence interval is 0.00541. There are 0 homozygotes in gnomad4. There are 256 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 571 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KANSL1	NM_015443.4	c.*954C>G		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.*954C>G		3_prime_UTR_variant	15/15	1	NM_015443.4	ENSP00000387393.3

Frequencies

GnomAD3 genomes AF: 0.00379 AC: 571 AN: 150548 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00115

Gnomad AMI AF: 0.0297

Gnomad AMR AF: 0.00331

Gnomad ASJ AF: 0.00519

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00168

Gnomad FIN AF: 0.00118

Gnomad MID AF: 0.00321

Gnomad NFE AF: 0.00588

Gnomad OTH AF: 0.00436

GnomAD4 exome AF: 0.0147 AC: 1 AN: 68 Hom.: 0 Cov.: 0 AF XY: 0.0227 AC XY: 1 AN XY: 44

Gnomad4 AFR exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0263

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00379 AC: 571 AN: 150668 Hom.: 0 Cov.: 31 AF XY: 0.00348 AC XY: 256 AN XY: 73484

Gnomad4 AFR AF: 0.00115

Gnomad4 AMR AF: 0.00331

Gnomad4 ASJ AF: 0.00519

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00168

Gnomad4 FIN AF: 0.00118

Gnomad4 NFE AF: 0.00588

Gnomad4 OTH AF: 0.00432

Alfa AF: 0.00328 Hom.: 0

Bravo AF: 0.00383

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2023	KANSL1: BS1 -
Uncertain significance, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	4.2
DANN	Benign	0.52
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs150500194; hg19: chr17-44107888;