rs1309097254

Variant names:

• chr17-46171069-T-C
• rs1309097254
• NM_015443.4:c.1075A>G

Your query was ambiguous. Multiple possible variants found:

• chr17-46171069-T-C
• chr17-46171069-T-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.1075A>G​(p.Ser359Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,854 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 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. S359R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 35)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: KANSL1 NM_015443.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 3.17
• 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: 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=0.113061756).

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.1075A>G	p.Ser359Gly	missense	Exon 2 of 15	NP_056258.1
	KANSL1	NM_001193466.2		c.1075A>G	p.Ser359Gly	missense	Exon 2 of 15	NP_001180395.1
	KANSL1	NM_001379198.1		c.1075A>G	p.Ser359Gly	missense	Exon 3 of 16	NP_001366127.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KANSL1	ENST00000432791.7	TSL:1 MANE Select	c.1075A>G	p.Ser359Gly	missense	Exon 2 of 15	ENSP00000387393.3
	KANSL1	ENST00000262419.10	TSL:1	c.1075A>G	p.Ser359Gly	missense	Exon 2 of 15	ENSP00000262419.6
	KANSL1	ENST00000572904.6	TSL:5	c.1075A>G	p.Ser359Gly	missense	Exon 2 of 15	ENSP00000461484.1

Frequencies

GnomAD3 genomes Cov.: 35

GnomAD2 exomes AF: 0.00 AC: 0 AN: 251438 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461854 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 727232

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53392

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1112004

Other (OTH) AF: 0.0000166 AC: 1 AN: 60394

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 35

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.53
CADD	Uncertain	24
DANN	Uncertain	0.99
Eigen	Benign	0.14
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Uncertain	0.86	D
M_CAP	Benign	0.0036	T
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-1.1	T
PhyloP100		3.2
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.063
Sift	Benign	0.13	T
Sift4G	Benign	0.20	T
Vest4		0.12
MutPred		0.14		Loss of phosphorylation at S359 (P = 0.0271)
MVP		0.17
MPC		0.040
ClinPred		0.37	T
GERP RS		4.8
PromoterAI		0.050	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
gMVP		0.099
Mutation Taster		=92/8	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.18		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: rs1309097254; hg19: chr17-44248435;