NM_015443.4:c.-89-3766C>T

Variant names:

• chr17-46175998-G-A
• rs2532259
• NM_015443.4:c.-89-3766C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_015443.4(KANSL1):​c.-89-3766C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.144 in 152,086 control chromosomes in the GnomAD database, including 2,138 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.14 (2138 hom., cov: 35)
• Consequence: KANSL1 NM_015443.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.51
• Publications: 13 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, Labcorp Genetics (formerly Invitae), ClinGen, G2P
• 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 (BayesDel_noAF=-0.85).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.215 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015443.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KANSL1	NM_015443.4	MANE Select	c.-89-3766C>T		intron	N/A	NP_056258.1	Q7Z3B3-1
	KANSL1	NM_001193466.2		c.-89-3766C>T		intron	N/A	NP_001180395.1	Q7Z3B3-1
	KANSL1	NM_001379198.1		c.-89-3766C>T		intron	N/A	NP_001366127.1	Q7Z3B3-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KANSL1	ENST00000432791.7	TSL:1 MANE Select	c.-89-3766C>T		intron	N/A	ENSP00000387393.3	Q7Z3B3-1
	KANSL1	ENST00000262419.10	TSL:1	c.-89-3766C>T		intron	N/A	ENSP00000262419.6	Q7Z3B3-1
	KANSL1	ENST00000918919.1		c.-89-3766C>T		intron	N/A	ENSP00000588978.1

Frequencies

GnomAD3 genomes AF: 0.144 AC: 21958 AN: 151966 Hom.: 2140 Cov.: 35

Gnomad AFR AF: 0.0433

Gnomad AMI AF: 0.305

Gnomad AMR AF: 0.178

Gnomad ASJ AF: 0.241

Gnomad EAS AF: 0.00154

Gnomad SAS AF: 0.0747

Gnomad FIN AF: 0.0659

Gnomad MID AF: 0.221

Gnomad NFE AF: 0.218

Gnomad OTH AF: 0.186

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.144 AC: 21947 AN: 152086 Hom.: 2138 Cov.: 35 AF XY: 0.135 AC XY: 10040 AN XY: 74348

African (AFR) AF: 0.0432 AC: 1794 AN: 41496

American (AMR) AF: 0.178 AC: 2713 AN: 15270

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

East Asian (EAS) AF: 0.00155 AC: 8 AN: 5168

South Asian (SAS) AF: 0.0748 AC: 361 AN: 4826

European-Finnish (FIN) AF: 0.0659 AC: 698 AN: 10590

Middle Eastern (MID) AF: 0.216 AC: 63 AN: 292

European-Non Finnish (NFE) AF: 0.218 AC: 14811 AN: 67956

Other (OTH) AF: 0.183 AC: 387 AN: 2114

Alfa AF: 0.196 Hom.: 1904

Bravo AF: 0.149

Asia WGS AF: 0.0310 AC: 109 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	11
DANN	Benign	0.74
PhyloP100		1.5
Mutation Taster		=100/0	polymorphism (auto)

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: rs2532259; hg19: chr17-44253364;