rs191058987

chr17-46170879-T-Achr17-46170879-T-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Moderate BP6_Very_Strong BS2

The NM_015443.4(KANSL1):c.1265A>T(p.Asp422Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000217 in 1,610,358 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 35)
  • Exomes 𝑓: 0.000023 (0 hom.)
• Consequence: KANSL1 NM_015443.4 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 7.46

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.09317109).
• BP6: Variant 17-46170879-T-A is Benign according to our data. Variant chr17-46170879-T-A is described in ClinVar as [Likely_benign]. Clinvar id is 205784.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAdExome at 31 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KANSL1	NM_015443.4	c.1265A>T	p.Asp422Val	missense_variant	2/15	ENST00000432791.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KANSL1	ENST00000432791.7	c.1265A>T	p.Asp422Val	missense_variant	2/15	1	NM_015443.4	P4

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152206 Hom.: 0 Cov.: 35

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000124 AC: 31 AN: 249584 Hom.: 0 AF XY: 0.0000593 AC XY: 8 AN XY: 135008

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000908

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: 0.0000226 AC: 33 AN: 1458034 Hom.: 0 Cov.: 30 AF XY: 0.0000110 AC XY: 8 AN XY: 724924

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000746

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 AF: 0.0000131 AC: 2 AN: 152324 Hom.: 0 Cov.: 35 AF XY: 0.0000268 AC XY: 2 AN XY: 74490

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000416

ExAC AF: 0.0000824 AC: 10

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Sep 28, 2015

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

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Aug 23, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.099	T
BayesDel_noAF	Uncertain	0.010
Cadd	Uncertain	25
Dann	Uncertain	0.99
Eigen	Uncertain	0.29
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Uncertain	0.96	D
M_CAP	Benign	0.066	D
MetaRNN	Benign	0.093	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Benign	0.41	T
PROVEAN	Uncertain	-3.8	D;.;.;.;.;D;.;.;.
REVEL	Uncertain	0.41
Sift	Uncertain	0.0030	D;.;.;.;.;D;.;.;.
Sift4G	Uncertain	0.0030	D;D;D;.;D;D;.;.;.
Vest4		0.68
MVP		0.41
MPC		0.15
ClinPred		0.16	T
GERP RS		5.2
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.7
gMVP		0.32

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: rs191058987; hg19: chr17-44248245;