17-46067627-G-T

Variant names:

• chr17-46067627-G-T
• rs144838667
• NM_015443.4:c.1574C>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_015443.4(KANSL1):​c.1574C>A​(p.Pro525His) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P525R) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: KANSL1 NM_015443.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.78
• Publications: 17 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.30307472).

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.1574C>A	p.Pro525His	missense	Exon 5 of 15	NP_056258.1
	KANSL1	NM_001193466.2		c.1574C>A	p.Pro525His	missense	Exon 5 of 15	NP_001180395.1
	KANSL1	NM_001379198.1		c.1574C>A	p.Pro525His	missense	Exon 6 of 16	NP_001366127.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KANSL1	ENST00000432791.7	TSL:1 MANE Select	c.1574C>A	p.Pro525His	missense	Exon 5 of 15	ENSP00000387393.3
	KANSL1	ENST00000262419.10	TSL:1	c.1574C>A	p.Pro525His	missense	Exon 5 of 15	ENSP00000262419.6
	KANSL1	ENST00000918919.1		c.1574C>A	p.Pro525His	missense	Exon 5 of 16	ENSP00000588978.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_noAF	Benign	-0.56
CADD	Benign	22
LIST_S2	Benign	0.65	T
MetaRNN	Benign	0.30	T
PhyloP100		3.8
Sift4G	Uncertain	0.016	D
Vest4		0.21
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
gMVP		0.22

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs144838667; hg19: chr17-44144993;