chr17-46171403-T-C

Variant names:

• chr17-46171403-T-C
• rs1881193
• NM_015443.4:c.741A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_015443.4(KANSL1):​c.741A>G​(p.Arg247Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.19 in 1,613,270 control chromosomes in the GnomAD database, including 32,772 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.15 (2139 hom., cov: 35)
  • Exomes 𝑓: 0.19 (30633 hom.)
• Consequence: KANSL1 NM_015443.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.963
• Publications: 24 publications found

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]

KANSL1 Gene-Disease associations (from GenCC):

• Koolen-de Vries syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), ClinGen
• Koolen-de Vries syndrome due to a point mutation

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.65).
• BP6: Variant 17-46171403-T-C is Benign according to our data. Variant chr17-46171403-T-C is described in ClinVar as Benign. ClinVar VariationId is 323787.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.963 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.215 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KANSL1	NM_015443.4	c.741A>G	p.Arg247Arg	synonymous_variant	Exon 2 of 15	ENST00000432791.7	NP_056258.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KANSL1	ENST00000432791.7	c.741A>G	p.Arg247Arg	synonymous_variant	Exon 2 of 15	1	NM_015443.4	ENSP00000387393.3

Frequencies

GnomAD3 genomes AF: 0.145 AC: 22105 AN: 152054 Hom.: 2141 Cov.: 35

Gnomad AFR AF: 0.0467

Gnomad AMI AF: 0.302

Gnomad AMR AF: 0.178

Gnomad ASJ AF: 0.241

Gnomad EAS AF: 0.00154

Gnomad SAS AF: 0.0749

Gnomad FIN AF: 0.0658

Gnomad MID AF: 0.223

Gnomad NFE AF: 0.218

Gnomad OTH AF: 0.186

GnomAD2 exomes AF: 0.146 AC: 36741 AN: 251096 AF XY: 0.150

Gnomad AFR exome AF: 0.0441

Gnomad AMR exome AF: 0.120

Gnomad ASJ exome AF: 0.255

Gnomad EAS exome AF: 0.000653

Gnomad FIN exome AF: 0.0689

Gnomad NFE exome AF: 0.215

Gnomad OTH exome AF: 0.176

GnomAD4 exome AF: 0.194 AC: 283979 AN: 1461096 Hom.: 30633 Cov.: 55 AF XY: 0.192 AC XY: 139475 AN XY: 726870

African (AFR) AF: 0.0403 AC: 1348 AN: 33474

American (AMR) AF: 0.126 AC: 5647 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.257 AC: 6714 AN: 26108

East Asian (EAS) AF: 0.000882 AC: 35 AN: 39700

South Asian (SAS) AF: 0.0798 AC: 6881 AN: 86214

European-Finnish (FIN) AF: 0.0731 AC: 3905 AN: 53396

Middle Eastern (MID) AF: 0.203 AC: 1168 AN: 5766

European-Non Finnish (NFE) AF: 0.223 AC: 247545 AN: 1111370

Other (OTH) AF: 0.178 AC: 10736 AN: 60366

GnomAD4 genome AF: 0.145 AC: 22094 AN: 152174 Hom.: 2139 Cov.: 35 AF XY: 0.136 AC XY: 10114 AN XY: 74398

African (AFR) AF: 0.0466 AC: 1936 AN: 41530

American (AMR) AF: 0.178 AC: 2716 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.241 AC: 836 AN: 3470

East Asian (EAS) AF: 0.00155 AC: 8 AN: 5172

South Asian (SAS) AF: 0.0749 AC: 362 AN: 4832

European-Finnish (FIN) AF: 0.0658 AC: 697 AN: 10594

Middle Eastern (MID) AF: 0.218 AC: 64 AN: 294

European-Non Finnish (NFE) AF: 0.218 AC: 14814 AN: 67984

Other (OTH) AF: 0.183 AC: 387 AN: 2110

Alfa AF: 0.186 Hom.: 2243

Bravo AF: 0.150

Asia WGS AF: 0.0310 AC: 110 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Apr 20, 2017

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Koolen-de Vries syndrome Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.65
CADD	Benign	8.9
DANN	Benign	0.58
PhyloP100		0.96
PromoterAI		0.0052	Neutral
Mutation Taster		=297/3	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1881193; hg19: chr17-44248769;