rs151099014

chr17-46039125-G-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_015443.4(KANSL1):c.2294C>T(p.Ala765Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000512 in 1,612,394 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00037 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00053 (1 hom.)
• Consequence: KANSL1 NM_015443.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 2.47

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.014103711).
• BP6: Variant 17-46039125-G-A is Benign according to our data. Variant chr17-46039125-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 323771.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd at 56 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KANSL1	NM_015443.4	c.2294C>T	p.Ala765Val	missense_variant	9/15	ENST00000432791.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KANSL1	ENST00000432791.7	c.2294C>T	p.Ala765Val	missense_variant	9/15	1	NM_015443.4	P4

Frequencies

GnomAD3 genomes AF: 0.000368 AC: 56 AN: 152212 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00132

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000470

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000529 AC: 132 AN: 249562 Hom.: 1 AF XY: 0.000511 AC XY: 69 AN XY: 135028

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000708

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00157

Gnomad NFE exome AF: 0.000583

Gnomad OTH exome AF: 0.000986

GnomAD4 exome AF: 0.000527 AC: 770 AN: 1460064 Hom.: 1 Cov.: 31 AF XY: 0.000511 AC XY: 371 AN XY: 726398

Gnomad4 AFR exome AF: 0.000120

Gnomad4 AMR exome AF: 0.000723

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00150

Gnomad4 NFE exome AF: 0.000562

Gnomad4 OTH exome AF: 0.000464

GnomAD4 genome AF: 0.000368 AC: 56 AN: 152330 Hom.: 0 Cov.: 32 AF XY: 0.000336 AC XY: 25 AN XY: 74504

Gnomad4 AFR AF: 0.0000721

Gnomad4 AMR AF: 0.000458

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00132

Gnomad4 NFE AF: 0.000470

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000449 Hom.: 0

Bravo AF: 0.000465

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.000560 AC: 68

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000764

EpiControl AF: 0.000711

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Nov 02, 2016	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 24, 2019	- -

Koolen-de Vries syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 27, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.58
Cadd	Benign	23
Dann	Benign	0.97
Eigen	Benign	-0.18
Eigen_PC	Benign	0.034
FATHMM_MKL	Uncertain	0.88	D
M_CAP	Benign	0.0041	T
MetaRNN	Benign	0.014	T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	0.96	D;D;D;D;D;D
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-1.1	N;.;.;N;.;.
REVEL	Benign	0.032
Sift	Benign	0.40	T;.;.;T;.;.
Sift4G	Benign	0.30	T;T;T;T;.;.
Vest4		0.19
MVP		0.043
MPC		0.46
ClinPred		0.018	T
GERP RS		5.0
gMVP		0.19

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: rs151099014; hg19: chr17-44116491;