rs547462953

chr17-46094568-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_015443.4(KANSL1):c.1423G>A(p.Ala475Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000435 in 1,612,748 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00028 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00045 (16 hom.)
• Consequence: KANSL1 NM_015443.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.26

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.007861078).
• BP6: Variant 17-46094568-C-T is Benign according to our data. Variant chr17-46094568-C-T is described in ClinVar as [Benign]. Clinvar id is 205733.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000276 (42/152324) while in subpopulation SAS AF= 0.0087 (42/4828). AF 95% confidence interval is 0.00661. There are 1 homozygotes in gnomad4. There are 32 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd at 42 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KANSL1	NM_015443.4	c.1423G>A	p.Ala475Thr	missense_variant	3/15	ENST00000432791.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KANSL1	ENST00000432791.7	c.1423G>A	p.Ala475Thr	missense_variant	3/15	1	NM_015443.4	P4

Frequencies

GnomAD3 genomes AF: 0.000276 AC: 42 AN: 152206 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00869

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000921 AC: 231 AN: 250878 Hom.: 3 AF XY: 0.00119 AC XY: 161 AN XY: 135630

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000292

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00732

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000982

GnomAD4 exome AF: 0.000452 AC: 660 AN: 1460424 Hom.: 16 Cov.: 31 AF XY: 0.000683 AC XY: 496 AN XY: 726570

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00730

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.000398

GnomAD4 genome AF: 0.000276 AC: 42 AN: 152324 Hom.: 1 Cov.: 33 AF XY: 0.000430 AC XY: 32 AN XY: 74476

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00870

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000671 Hom.: 0

Bravo AF: 0.0000227

ExAC AF: 0.00105 AC: 127

Asia WGS AF: 0.00318 AC: 11 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jan 27, 2017

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Aug 04, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.23
Cadd	Uncertain	25
Dann	Pathogenic	1.0
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Uncertain	0.88	D
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.0079	T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.58	T
MutationTaster	Benign	0.71	D;D;D;D;D;D
PrimateAI	Uncertain	0.60	T
PROVEAN	Uncertain	-2.5	N;.;.;.;.;N;.;.;.;.
REVEL	Benign	0.18
Sift	Benign	0.099	T;.;.;.;.;T;.;.;.;.
Sift4G	Benign	0.29	T;T;T;.;T;T;.;.;.;.
Vest4		0.59
MutPred		0.24		Gain of methylation at K471 (P = 0.0633);Gain of methylation at K471 (P = 0.0633);Gain of methylation at K471 (P = 0.0633);Gain of methylation at K471 (P = 0.0633);Gain of methylation at K471 (P = 0.0633);Gain of methylation at K471 (P = 0.0633);Gain of methylation at K471 (P = 0.0633);Gain of methylation at K471 (P = 0.0633);.;Gain of methylation at K471 (P = 0.0633);
MVP		0.59
MPC		0.96
ClinPred		0.062	T
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
gMVP		0.42

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: rs547462953; hg19: chr17-44171934;