NM_015443.4:c.2503C>T

Variant names:

• chr17-46038576-G-A
• rs1555733519
• NM_015443.4:c.2503C>T

Variant summary

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

Score: -1 - Likely Benign

-1

PM2BP4_ModerateBP6

The NM_015443.4(KANSL1):​c.2503C>T​(p.Pro835Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,461,862 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P835L) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: KANSL1 NM_015443.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 6.42
• 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=0.1718407).
• BP6: Variant 17-46038576-G-A is Benign according to our data. Variant chr17-46038576-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 508468.We mark this variant Likely_benign, oryginal submission is: [Conflicting_classifications_of_pathogenicity].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KANSL1	NM_015443.4	c.2503C>T	p.Pro835Ser	missense_variant	Exon 10 of 15	ENST00000432791.7	NP_056258.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KANSL1	ENST00000432791.7	c.2503C>T	p.Pro835Ser	missense_variant	Exon 10 of 15	1	NM_015443.4	ENSP00000387393.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461862 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727234

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53408

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111998

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Koolen-de Vries syndrome Uncertain:1

Aug 13, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

Mar 31, 2017

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	21
DANN	Benign	0.70
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.31
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.81	.;.;.;.;T;T;T;T;T;T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.17	T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
PhyloP100		6.4
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-1.1	N;.;.;.;.;N;.;.;.;.
REVEL	Benign	0.076
Sift	Benign	0.11	T;.;.;.;.;T;.;.;.;.
Sift4G	Benign	0.51	T;T;T;.;T;T;.;.;.;.
Vest4		0.28
MutPred		0.23		Gain of phosphorylation at P835 (P = 0.0031);Gain of phosphorylation at P835 (P = 0.0031);Gain of phosphorylation at P835 (P = 0.0031);.;.;Gain of phosphorylation at P835 (P = 0.0031);Gain of phosphorylation at P835 (P = 0.0031);.;.;.;
MVP		0.082
MPC		0.47
ClinPred		0.13	T
GERP RS		4.0
gMVP		0.54
Mutation Taster		=48/52	disease causing

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

Other links and lift over

dbSNP: rs1555733519; hg19: chr17-44115942;