rs34101027

Positions:

• chr17-46039796-T-A
• chr17-46039796-T-C
• chr17-46039796-T-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The ENST00000432791.7(KANSL1):​c.2109A>T​(p.Leu703Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,890 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. L703L) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: KANSL1 ENST00000432791.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.177

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 -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.050435662).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KANSL1	NM_015443.4	c.2109A>T	p.Leu703Phe	missense_variant	8/15	ENST00000432791.7	NP_056258.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KANSL1	ENST00000432791.7	c.2109A>T	p.Leu703Phe	missense_variant	8/15	1	NM_015443.4	ENSP00000387393	P4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251488 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135922

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461890 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727246

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Koolen-de Vries syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 28, 2018

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The phenylalanine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with KANSL1-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces leucine with phenylalanine at codon 703 of the KANSL1 protein (p.Leu703Phe). The leucine residue is moderately conserved and there is a small physicochemical difference between leucine and phenylalanine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	10
DANN	Benign	0.61
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.31	N
LIST_S2	Benign	0.80	.;.;.;.;T;T;T;T;T
M_CAP	Benign	0.0041	T
MetaRNN	Benign	0.050	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	0.94	N;N;N;N;N;N
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.98	N;.;.;.;.;N;.;.;.
REVEL	Benign	0.21
Sift	Benign	0.42	T;.;.;.;.;T;.;.;.
Sift4G	Benign	0.15	T;T;T;.;T;T;.;.;.
Vest4		0.058
MutPred		0.17		Gain of methylation at K702 (P = 0.0548);Gain of methylation at K702 (P = 0.0548);Gain of methylation at K702 (P = 0.0548);Gain of methylation at K702 (P = 0.0548);Gain of methylation at K702 (P = 0.0548);Gain of methylation at K702 (P = 0.0548);Gain of methylation at K702 (P = 0.0548);Gain of methylation at K702 (P = 0.0548);.;
MVP		0.14
MPC		0.52
ClinPred		0.032	T
GERP RS		-1.6
gMVP		0.10

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: rs34101027; hg19: chr17-44117162;