rs17574604

chr17-46034247-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_015443.4(KANSL1):c.2580T>C(p.Phe860=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.189 in 1,613,590 control chromosomes in the GnomAD database, including 32,776 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.14 (2136 hom., cov: 32)
  • Exomes 𝑓: 0.19 (30640 hom.)
• Consequence: KANSL1 NM_015443.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.635

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 17-46034247-A-G is Benign according to our data. Variant chr17-46034247-A-G is described in ClinVar as [Benign]. Clinvar id is 323767.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-46034247-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.635 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.214 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KANSL1	NM_015443.4	c.2580T>C	p.Phe860=	synonymous_variant	11/15	ENST00000432791.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KANSL1	ENST00000432791.7	c.2580T>C	p.Phe860=	synonymous_variant	11/15	1	NM_015443.4	P4

Frequencies

GnomAD3 genomes AF: 0.143 AC: 21812 AN: 152136 Hom.: 2138 Cov.: 32

Gnomad AFR AF: 0.0429

Gnomad AMI AF: 0.278

Gnomad AMR AF: 0.176

Gnomad ASJ AF: 0.240

Gnomad EAS AF: 0.00154

Gnomad SAS AF: 0.0736

Gnomad FIN AF: 0.0649

Gnomad MID AF: 0.218

Gnomad NFE AF: 0.217

Gnomad OTH AF: 0.184

GnomAD3 exomes AF: 0.145 AC: 36448 AN: 251234 Hom.: 3539 AF XY: 0.149 AC XY: 20176 AN XY: 135770

Gnomad AFR exome AF: 0.0398

Gnomad AMR exome AF: 0.119

Gnomad ASJ exome AF: 0.254

Gnomad EAS exome AF: 0.000652

Gnomad SAS exome AF: 0.0759

Gnomad FIN exome AF: 0.0681

Gnomad NFE exome AF: 0.213

Gnomad OTH exome AF: 0.175

GnomAD4 exome AF: 0.193 AC: 282555 AN: 1461336 Hom.: 30640 Cov.: 32 AF XY: 0.191 AC XY: 138803 AN XY: 726990

Gnomad4 AFR exome AF: 0.0365

Gnomad4 AMR exome AF: 0.125

Gnomad4 ASJ exome AF: 0.256

Gnomad4 EAS exome AF: 0.000882

Gnomad4 SAS exome AF: 0.0795

Gnomad4 FIN exome AF: 0.0724

Gnomad4 NFE exome AF: 0.222

Gnomad4 OTH exome AF: 0.177

GnomAD4 genome AF: 0.143 AC: 21801 AN: 152254 Hom.: 2136 Cov.: 32 AF XY: 0.134 AC XY: 9973 AN XY: 74430

Gnomad4 AFR AF: 0.0428

Gnomad4 AMR AF: 0.175

Gnomad4 ASJ AF: 0.240

Gnomad4 EAS AF: 0.00154

Gnomad4 SAS AF: 0.0736

Gnomad4 FIN AF: 0.0649

Gnomad4 NFE AF: 0.217

Gnomad4 OTH AF: 0.181

Alfa AF: 0.203 Hom.: 3397

Bravo AF: 0.148

Asia WGS AF: 0.0310 AC: 109 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 20, 2017	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

Koolen-de Vries syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
Cadd	Benign	1.6
Dann	Benign	0.54
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs17574604; hg19: chr17-44111613; COSMIC: COSV52274749; COSMIC: COSV52274749;