rs35643216

Variant names:

• chr17-46171471-T-C
• rs35643216
• NM_015443.4:c.673A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BP6_Very_Strong

The NM_015443.4(KANSL1):​c.673A>G​(p.Asn225Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.148 in 1,568,724 control chromosomes in the GnomAD database, with no homozygous occurrence. There is a variant allele frequency bias in the population database for this variant (GnomAd4), which may indicate mosaicism or somatic mutations in the reference population data. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N225S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.11 (0 hom., cov: 35)
  • Exomes 𝑓: 0.15 (0 hom.)
• Consequence: KANSL1 NM_015443.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 2.62
• Publications: 23 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.001316905).
• BP6: Variant 17-46171471-T-C is Benign according to our data. Variant chr17-46171471-T-C is described in ClinVar as Benign. ClinVar VariationId is 323790.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KANSL1	NM_015443.4	c.673A>G	p.Asn225Asp	missense_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.673A>G	p.Asn225Asp	missense_variant	Exon 2 of 15	1	NM_015443.4	ENSP00000387393.3

Frequencies

GnomAD3 genomes AF: 0.115 AC: 17185 AN: 149994 Hom.: 0 Cov.: 35

Gnomad AFR AF: 0.0345

Gnomad AMI AF: 0.248

Gnomad AMR AF: 0.143

Gnomad ASJ AF: 0.181

Gnomad EAS AF: 0.00116

Gnomad SAS AF: 0.0529

Gnomad FIN AF: 0.0564

Gnomad MID AF: 0.171

Gnomad NFE AF: 0.174

Gnomad OTH AF: 0.149

GnomAD2 exomes AF: 0.113 AC: 27969 AN: 246450 AF XY: 0.115

Gnomad AFR exome AF: 0.0318

Gnomad AMR exome AF: 0.0983

Gnomad ASJ exome AF: 0.177

Gnomad EAS exome AF: 0.000598

Gnomad FIN exome AF: 0.0583

Gnomad NFE exome AF: 0.170

Gnomad OTH exome AF: 0.139

GnomAD4 exome AF: 0.152 AC: 215603 AN: 1418612 Hom.: 0 Cov.: 49 AF XY: 0.150 AC XY: 105724 AN XY: 706244

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0296 AC: 990 AN: 33422

American (AMR) AF: 0.104 AC: 4620 AN: 44220

Ashkenazi Jewish (ASJ) AF: 0.188 AC: 4737 AN: 25260

East Asian (EAS) AF: 0.000831 AC: 33 AN: 39700

South Asian (SAS) AF: 0.0550 AC: 4663 AN: 84802

European-Finnish (FIN) AF: 0.0650 AC: 3453 AN: 53120

Middle Eastern (MID) AF: 0.150 AC: 857 AN: 5698

European-Non Finnish (NFE) AF: 0.175 AC: 187933 AN: 1073434

Other (OTH) AF: 0.141 AC: 8317 AN: 58956

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.114 AC: 17172 AN: 150112 Hom.: 0 Cov.: 35 AF XY: 0.107 AC XY: 7852 AN XY: 73394

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0344 AC: 1425 AN: 41412

American (AMR) AF: 0.143 AC: 2144 AN: 15044

Ashkenazi Jewish (ASJ) AF: 0.181 AC: 613 AN: 3390

East Asian (EAS) AF: 0.00116 AC: 6 AN: 5164

South Asian (SAS) AF: 0.0527 AC: 252 AN: 4778

European-Finnish (FIN) AF: 0.0564 AC: 594 AN: 10526

Middle Eastern (MID) AF: 0.163 AC: 47 AN: 288

European-Non Finnish (NFE) AF: 0.174 AC: 11564 AN: 66546

Other (OTH) AF: 0.147 AC: 304 AN: 2066

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.143 Hom.: 172

ESP6500AA AF: 0.0379 AC: 167

ESP6500EA AF: 0.182 AC: 1565

ExAC AF: 0.120 AC: 14625

Asia WGS AF: 0.0250 AC: 87 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

- -

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
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	21
DANN	Uncertain	0.99
Eigen	Benign	-0.071
Eigen_PC	Benign	0.14
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.90	.;.;.;.;D;D;D;D;D
MetaRNN	Benign	0.0013	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.71	T
PhyloP100		2.6
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-0.33	N;.;.;.;.;N;.;.;.
REVEL	Benign	0.058
Sift	Benign	0.14	T;.;.;.;.;T;.;.;.
Sift4G	Benign	0.64	T;T;T;.;T;T;.;.;.
Vest4		0.20
MPC		0.020
ClinPred		0.0047	T
GERP RS		5.0
PromoterAI		0.0086	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
gMVP		0.13
Mutation Taster		=95/5	polymorphism

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

Other links and lift over

dbSNP: rs35643216; hg19: chr17-44248837; COSMIC: COSV52264978; COSMIC: COSV52264978;