rs149566146

chr17-46171573-C-A

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.571G>T(p.Gly191Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000666 in 1,604,922 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00039 (0 hom., cov: 35)
  • Exomes 𝑓: 0.00070 (0 hom.)
• Consequence: KANSL1 NM_015443.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.61

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=0.040864676).
• BP6: Variant 17-46171573-C-A is Benign according to our data. Variant chr17-46171573-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 205770.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.000695 (1010/1452680) while in subpopulation NFE AF= 0.000886 (982/1108088). AF 95% confidence interval is 0.00084. There are 0 homozygotes in gnomad4_exome. There are 472 alleles in male gnomad4_exome subpopulation. Median coverage is 35. This position pass quality control queck.
• BS2: High AC in GnomAd at 59 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KANSL1	NM_015443.4	c.571G>T	p.Gly191Cys	missense_variant	2/15	ENST00000432791.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KANSL1	ENST00000432791.7	c.571G>T	p.Gly191Cys	missense_variant	2/15	1	NM_015443.4	P4

Frequencies

GnomAD3 genomes AF: 0.000388 AC: 59 AN: 152124 Hom.: 0 Cov.: 35

Gnomad AFR AF: 0.000290

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

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: 0.000647

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000265 AC: 64 AN: 241888 Hom.: 0 AF XY: 0.000252 AC XY: 33 AN XY: 130920

Gnomad AFR exome AF: 0.000187

Gnomad AMR exome AF: 0.0000306

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: 0.000545

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000695 AC: 1010 AN: 1452680 Hom.: 0 Cov.: 35 AF XY: 0.000653 AC XY: 472 AN XY: 722500

Gnomad4 AFR exome AF: 0.000121

Gnomad4 AMR exome AF: 0.0000234

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000189

Gnomad4 NFE exome AF: 0.000886

Gnomad4 OTH exome AF: 0.000367

GnomAD4 genome AF: 0.000388 AC: 59 AN: 152242 Hom.: 0 Cov.: 35 AF XY: 0.000336 AC XY: 25 AN XY: 74418

Gnomad4 AFR AF: 0.000289

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000647

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000715 Hom.: 0

Bravo AF: 0.000389

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000165 AC: 20

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2023	KANSL1: BP4 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 21, 2021	- -

Koolen-de Vries syndrome Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Oct 13, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jul 19, 2021	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Jun 22, 2017

- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 04, 2022

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.094
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.51
Cadd	Benign	14
Dann	Uncertain	0.98
Eigen	Benign	-0.28
Eigen_PC	Benign	-0.21
FATHMM_MKL	Uncertain	0.81	D
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.041	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	0.98	D;N;N;N;N;N
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.79	N;.;.;.;.;N;.;.;.
REVEL	Benign	0.086
Sift	Benign	0.096	T;.;.;.;.;T;.;.;.
Sift4G	Benign	0.078	T;T;T;.;D;T;.;.;.
Vest4		0.32
MVP		0.20
MPC		0.073
ClinPred		0.027	T
GERP RS		3.0
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: rs149566146; hg19: chr17-44248939;