17-46171614-T-A

Variant names:

• chr17-46171614-T-A
• rs765213873
• NM_015443.4:c.530A>T

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP4

The NM_015443.4(KANSL1):​c.530A>T​(p.Asn177Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00000421 in 1,425,230 control chromosomes in the GnomAD database, with no homozygous occurrence. There is a variant allele frequency bias in the population database for this variant (GnomAdExome4), which may indicate mosaicism or somatic mutations in the reference population data. 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. N177S) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 35)
  • Exomes 𝑓: 0.0000042 (0 hom.)
• Consequence: KANSL1 NM_015443.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.36
• Publications: 1 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: Likely_benign. The variant received -1 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.31812567).

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.530A>T	p.Asn177Ile	missense	Exon 2 of 15	NP_056258.1	Q7Z3B3-1
	KANSL1	NM_001193466.2		c.530A>T	p.Asn177Ile	missense	Exon 2 of 15	NP_001180395.1	Q7Z3B3-1
	KANSL1	NM_001379198.1		c.530A>T	p.Asn177Ile	missense	Exon 3 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.530A>T	p.Asn177Ile	missense	Exon 2 of 15	ENSP00000387393.3	Q7Z3B3-1
	KANSL1	ENST00000262419.10	TSL:1	c.530A>T	p.Asn177Ile	missense	Exon 2 of 15	ENSP00000262419.6	Q7Z3B3-1
	KANSL1	ENST00000918919.1		c.530A>T	p.Asn177Ile	missense	Exon 2 of 16	ENSP00000588978.1

Frequencies

GnomAD3 genomes Cov.: 35

GnomAD2 exomes AF: 0.00000922 AC: 2 AN: 216862 AF XY: 0.00000853

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: 0.0000197

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000421 AC: 6 AN: 1425230 Hom.: 0 Cov.: 35 AF XY: 0.00000141 AC XY: 1 AN XY: 707410

⚠️ 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: 31630

American (AMR) AF: 0.00 AC: 0 AN: 36536

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23374

East Asian (EAS) AF: 0.00 AC: 0 AN: 39420

South Asian (SAS) AF: 0.00 AC: 0 AN: 81382

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51378

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5548

European-Non Finnish (NFE) AF: 0.00000547 AC: 6 AN: 1097244

Other (OTH) AF: 0.00 AC: 0 AN: 58718

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000116339), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 35

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.45
BayesDel_addAF	Benign	-0.017	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	22
DANN	Uncertain	0.99
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.055	D
MetaRNN	Benign	0.32	T
MetaSVM	Benign	-1.1	T
PhyloP100		5.4
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-2.3	N
REVEL	Benign	0.21
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0020	D
Vest4		0.78
MutPred		0.24		Loss of solvent accessibility (P = 0.0058)
MVP		0.28
MPC		0.15
ClinPred		0.88	D
GERP RS		5.0
PromoterAI		0.0086	Neutral
gMVP		0.55
Mutation Taster		=79/21	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: rs765213873; hg19: chr17-44248980;