17-46067576-A-T

Variant names:

• chr17-46067576-A-T
• rs796052593
• NM_015443.4:c.1625T>A

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BP6

The NM_015443.4(KANSL1):​c.1625T>A​(p.Leu542His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000207 in 1,450,244 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: KANSL1 NM_015443.4 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.15
• Publications: 0 publications found

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]

KANSL1 Gene-Disease associations (from GenCC):

• Koolen-de Vries syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), ClinGen
• Koolen-de Vries syndrome due to a point mutation

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15579316).
• BP6: Variant 17-46067576-A-T is Benign according to our data. Variant chr17-46067576-A-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 205790.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KANSL1	NM_015443.4	c.1625T>A	p.Leu542His	missense_variant	Exon 5 of 15	ENST00000432791.7	NP_056258.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KANSL1	ENST00000432791.7	c.1625T>A	p.Leu542His	missense_variant	Exon 5 of 15	1	NM_015443.4	ENSP00000387393.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000207 AC: 3 AN: 1450244 Hom.: 0 Cov.: 28 AF XY: 0.00000138 AC XY: 1 AN XY: 722226

⚠️ 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: 33214

American (AMR) AF: 0.00 AC: 0 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26050

East Asian (EAS) AF: 0.00 AC: 0 AN: 39630

South Asian (SAS) AF: 0.0000349 AC: 3 AN: 86030

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5754

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1101442

Other (OTH) AF: 0.00 AC: 0 AN: 60012

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0232839), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Sep 27, 2015

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Koolen-de Vries syndrome Benign:1

Dec 01, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	23
DANN	Benign	0.94
Eigen	Benign	-0.066
Eigen_PC	Benign	0.030
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.82	.;.;.;.;T;D;T;T;T;T
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.16	T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
PhyloP100		2.1
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.22	N;.;.;.;.;N;.;.;.;.
REVEL	Benign	0.071
Sift	Benign	0.38	T;.;.;.;.;T;.;.;.;.
Sift4G	Benign	0.21	T;T;T;.;T;T;.;.;.;.
Vest4		0.40
MutPred		0.31		Loss of stability (P = 0.0136);Loss of stability (P = 0.0136);Loss of stability (P = 0.0136);Loss of stability (P = 0.0136);Loss of stability (P = 0.0136);Loss of stability (P = 0.0136);Loss of stability (P = 0.0136);Loss of stability (P = 0.0136);.;Loss of stability (P = 0.0136);
MVP		0.37
MPC		1.3
ClinPred		0.30	T
GERP RS		4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
gMVP		0.16
Mutation Taster		=93/7	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs796052593; hg19: chr17-44144942;