chr17-46171524-T-C

Position:

• chr17-46171524-T-C

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_015443.4(KANSL1):​c.620A>G​(p.Asn207Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000442 in 1,613,538 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00019 (0 hom., cov: 35)
  • Exomes 𝑓: 0.00047 (0 hom.)
• Consequence: KANSL1 NM_015443.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 3.92

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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.100685716).
• BP6: Variant 17-46171524-T-C is Benign according to our data. Variant chr17-46171524-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 205806.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-46171524-T-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000191 (29/152126) while in subpopulation NFE AF= 0.000353 (24/68042). AF 95% confidence interval is 0.000243. There are 0 homozygotes in gnomad4. There are 16 alleles in male gnomad4 subpopulation. Median coverage is 35. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 29 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KANSL1	NM_015443.4	c.620A>G	p.Asn207Ser	missense_variant	2/15	ENST00000432791.7	NP_056258.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KANSL1	ENST00000432791.7	c.620A>G	p.Asn207Ser	missense_variant	2/15	1	NM_015443.4	ENSP00000387393.3

Frequencies

GnomAD3 genomes AF: 0.000191 AC: 29 AN: 152126 Hom.: 0 Cov.: 35

Gnomad AFR AF: 0.0000725

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000353

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000255 AC: 64 AN: 251040 Hom.: 0 AF XY: 0.000243 AC XY: 33 AN XY: 135670

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000528

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.000468 AC: 684 AN: 1461412 Hom.: 0 Cov.: 35 AF XY: 0.000424 AC XY: 308 AN XY: 727006

Gnomad4 AFR exome AF: 0.000119

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.0000562

Gnomad4 NFE exome AF: 0.000587

Gnomad4 OTH exome AF: 0.000364

GnomAD4 genome AF: 0.000191 AC: 29 AN: 152126 Hom.: 0 Cov.: 35 AF XY: 0.000215 AC XY: 16 AN XY: 74320

Gnomad4 AFR AF: 0.0000725

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.000353

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000299 Hom.: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000313 AC: 38

EpiCase AF: 0.000327

EpiControl AF: 0.000356

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:5

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Dec 23, 2015	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2023	KANSL1: BP4 -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 27, 2020	- -

Koolen-de Vries syndrome Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 16, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Aug 27, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	22
DANN	Uncertain	0.98
Eigen	Uncertain	0.22
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Uncertain	0.94	.;.;.;.;D;D;D;D;D
M_CAP	Benign	0.0051	T
MetaRNN	Benign	0.10	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-0.65	N;.;.;.;.;N;.;.;.
REVEL	Benign	0.10
Sift	Benign	0.063	T;.;.;.;.;T;.;.;.
Sift4G	Benign	0.32	T;T;T;.;T;T;.;.;.
Vest4		0.53
MVP		0.12
MPC		0.033
ClinPred		0.028	T
GERP RS		6.0
gMVP		0.16

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: rs144882998; hg19: chr17-44248890; COSMIC: COSV52266481; COSMIC: COSV52266481;