chr17-46033166-G-C

Position:

• chr17-46033166-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_015443.4(KANSL1):​c.2751C>G​(p.Phe917Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. F917F) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: KANSL1 NM_015443.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0610

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 Uncertain_significance. Variant got 4 ACMG points.

• PM1: In a mutagenesis_site No effect on interaction with KAT8. (size 0) in uniprot entity KANL1_HUMAN
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KANSL1	NM_015443.4	c.2751C>G	p.Phe917Leu	missense_variant	13/15	ENST00000432791.7	NP_056258.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KANSL1	ENST00000432791.7	c.2751C>G	p.Phe917Leu	missense_variant	13/15	1	NM_015443.4	ENSP00000387393	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.10
CADD	Benign	11
DANN	Uncertain	0.99
Eigen	Benign	-0.16
Eigen_PC	Benign	-0.32
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.96	.;.;.;.;D;D;D;D;D;D
M_CAP	Benign	0.036	D
MetaRNN	Uncertain	0.71	D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.46	T
MutationTaster	Benign	0.99	D;D;D;D;D;D
PrimateAI	Pathogenic	0.84	D
PROVEAN	Uncertain	-3.8	D;.;.;.;.;D;.;.;.;.
REVEL	Uncertain	0.39
Sift	Uncertain	0.010	D;.;.;.;.;D;.;.;.;.
Sift4G	Benign	0.10	.;T;.;.;T;T;.;.;.;.
Vest4		0.95, 0.94, 0.95
MutPred		0.52		Loss of catalytic residue at F917 (P = 0.0022);Loss of catalytic residue at F917 (P = 0.0022);.;.;.;Loss of catalytic residue at F917 (P = 0.0022);Loss of catalytic residue at F917 (P = 0.0022);.;.;.;
MVP		0.73
MPC		1.5
ClinPred		0.99	D
GERP RS		-5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
gMVP		0.70

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: rs36076725; hg19: chr17-44110532;