NM_015443.4:c.2725-7A>G

Variant names:

• chr17-46033199-T-C
• rs186818985
• NM_015443.4:c.2725-7A>G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_015443.4(KANSL1):​c.2725-7A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000265 in 1,583,504 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00030 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00026 (2 hom.)
• Consequence: KANSL1 NM_015443.4 splice_region, intron
• Scores: Splicing: ADA: 0.00001811
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: -2.25
• Publications: 0 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 17-46033199-T-C is Benign according to our data. Variant chr17-46033199-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 205749.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000302 (46/152250) while in subpopulation SAS AF = 0.00166 (8/4818). AF 95% confidence interval is 0.000826. There are 0 homozygotes in GnomAd4. There are 25 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 46 AD gene.

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.2725-7A>G		splice_region intron	N/A	NP_056258.1	Q7Z3B3-1
	KANSL1	NM_001193466.2		c.2725-7A>G		splice_region intron	N/A	NP_001180395.1	Q7Z3B3-1
	KANSL1	NM_001379198.1		c.2725-7A>G		splice_region 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.2725-7A>G		splice_region intron	N/A	ENSP00000387393.3	Q7Z3B3-1
	KANSL1	ENST00000262419.10	TSL:1	c.2725-7A>G		splice_region intron	N/A	ENSP00000262419.6	Q7Z3B3-1
	KANSL1	ENST00000572218.5	TSL:1	n.6942-7A>G		splice_region intron	N/A

Frequencies

GnomAD3 genomes AF: 0.000302 AC: 46 AN: 152132 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000966

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000916

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000279

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000435 AC: 92 AN: 211564 AF XY: 0.000449

Gnomad AFR exome AF: 0.0000757

Gnomad AMR exome AF: 0.000807

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000284

Gnomad OTH exome AF: 0.000746

GnomAD4 exome AF: 0.000261 AC: 374 AN: 1431254 Hom.: 2 Cov.: 29 AF XY: 0.000270 AC XY: 192 AN XY: 710258

African (AFR) AF: 0.000152 AC: 5 AN: 32956

American (AMR) AF: 0.000763 AC: 32 AN: 41940

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25468

East Asian (EAS) AF: 0.0000516 AC: 2 AN: 38782

South Asian (SAS) AF: 0.00129 AC: 107 AN: 83018

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51916

Middle Eastern (MID) AF: 0.00279 AC: 16 AN: 5728

European-Non Finnish (NFE) AF: 0.000161 AC: 176 AN: 1092174

Other (OTH) AF: 0.000607 AC: 36 AN: 59272

GnomAD4 genome AF: 0.000302 AC: 46 AN: 152250 Hom.: 0 Cov.: 32 AF XY: 0.000336 AC XY: 25 AN XY: 74436

African (AFR) AF: 0.0000963 AC: 4 AN: 41550

American (AMR) AF: 0.000915 AC: 14 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.00166 AC: 8 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000279 AC: 19 AN: 68014

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.000264 Hom.: 0

Bravo AF: 0.000249

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	not provided (2)
-	-	2	not specified (2)
-	-	1	Koolen-de Vries syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.76
DANN	Benign	0.41
PhyloP100		-2.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000018
dbscSNV1_RF	Benign	0.0020
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: rs186818985; hg19: chr17-44110565;