rs1555734253

Variant names:

• chr17-46039872-C-T
• rs1555734253
• NM_015443.4:c.2033G>A

Your query was ambiguous. Multiple possible variants found:

• chr17-46039872-C-T
• chr17-46039872-C-G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_015443.4(KANSL1):​c.2033G>A​(p.Ser678Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S678R) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: KANSL1 NM_015443.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.82
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.18529162).

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.2033G>A	p.Ser678Asn	missense	Exon 8 of 15	NP_056258.1	Q7Z3B3-1
	KANSL1	NM_001193466.2		c.2033G>A	p.Ser678Asn	missense	Exon 8 of 15	NP_001180395.1	Q7Z3B3-1
	KANSL1	NM_001379198.1		c.2033G>A	p.Ser678Asn	missense	Exon 9 of 16	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.2033G>A	p.Ser678Asn	missense	Exon 8 of 15	ENSP00000387393.3	Q7Z3B3-1
	KANSL1	ENST00000262419.10	TSL:1	c.2033G>A	p.Ser678Asn	missense	Exon 8 of 15	ENSP00000262419.6	Q7Z3B3-1
	KANSL1	ENST00000572218.5	TSL:1	n.6250G>A		non_coding_transcript_exon	Exon 1 of 8

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Koolen-de Vries syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	23
DANN	Benign	0.80
Eigen	Benign	-0.16
Eigen_PC	Benign	0.019
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.79	T
M_CAP	Benign	0.0031	T
MetaRNN	Benign	0.19	T
MetaSVM	Benign	-1.1	T
PhyloP100		2.8
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-0.51	N
REVEL	Benign	0.047
Sift	Benign	0.57	T
Sift4G	Benign	0.55	T
Vest4		0.30
MutPred		0.53		Gain of catalytic residue at S678 (P = 0.045)
MVP		0.093
MPC		0.49
ClinPred		0.30	T
GERP RS		4.5
gMVP		0.23
Mutation Taster		=87/13	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: rs1555734253; hg19: chr17-44117238;