17-46032305-C-T

Variant names:

• chr17-46032305-C-T
• rs1555730956
• NM_015443.4:c.2838-6G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_015443.4(KANSL1):​c.2838-6G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000741 in 1,349,426 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 7.4e-7 (0 hom.)
• Consequence: KANSL1 NM_015443.4 splice_region, intron
• Scores: Splicing: ADA: 0.0005197
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.717
• 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, 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KANSL1	NM_015443.4	MANE Select	c.2838-6G>A		splice_region intron	N/A	NP_056258.1
	KANSL1	NM_001193466.2		c.2838-6G>A		splice_region intron	N/A	NP_001180395.1
	KANSL1	NM_001379198.1		c.2838-6G>A		splice_region intron	N/A	NP_001366127.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KANSL1	ENST00000432791.7	TSL:1 MANE Select	c.2838-6G>A		splice_region intron	N/A	ENSP00000387393.3
	KANSL1	ENST00000262419.10	TSL:1	c.2838-6G>A		splice_region intron	N/A	ENSP00000262419.6
	KANSL1	ENST00000572218.5	TSL:1	n.7055-6G>A		splice_region intron	N/A

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 7.41e-7 AC: 1 AN: 1349426 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 660008

African (AFR) AF: 0.00 AC: 0 AN: 30114

American (AMR) AF: 0.00 AC: 0 AN: 29010

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19652

East Asian (EAS) AF: 0.00 AC: 0 AN: 38038

South Asian (SAS) AF: 0.00 AC: 0 AN: 69232

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 42638

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5276

European-Non Finnish (NFE) AF: 9.44e-7 AC: 1 AN: 1059814

Other (OTH) AF: 0.00 AC: 0 AN: 55652

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	4.4
DANN	Benign	0.70
PhyloP100		-0.72

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00052
dbscSNV1_RF	Benign	0.0040
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: rs1555730956; hg19: chr17-44109671;