17-46171644-T-G

Variant names:

• chr17-46171644-T-G
• rs779594202
• NM_015443.4:c.500A>C

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BP6

The NM_015443.4(KANSL1):​c.500A>C​(p.His167Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000712 in 1,404,870 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H167R) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 35)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: KANSL1 NM_015443.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 2.07
• 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 -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13725495).
• BP6: Variant 17-46171644-T-G is Benign according to our data. Variant chr17-46171644-T-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 380345.

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.500A>C	p.His167Pro	missense	Exon 2 of 15	NP_056258.1
	KANSL1	NM_001193466.2		c.500A>C	p.His167Pro	missense	Exon 2 of 15	NP_001180395.1
	KANSL1	NM_001379198.1		c.500A>C	p.His167Pro	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.500A>C	p.His167Pro	missense	Exon 2 of 15	ENSP00000387393.3
	KANSL1	ENST00000262419.10	TSL:1	c.500A>C	p.His167Pro	missense	Exon 2 of 15	ENSP00000262419.6
	KANSL1	ENST00000572904.6	TSL:5	c.500A>C	p.His167Pro	missense	Exon 2 of 15	ENSP00000461484.1

Frequencies

GnomAD3 genomes Cov.: 35

GnomAD2 exomes AF: 0.00000496 AC: 1 AN: 201436 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000411

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: 7.12e-7 AC: 1 AN: 1404870 Hom.: 0 Cov.: 35 AF XY: 0.00 AC XY: 0 AN XY: 694916

African (AFR) AF: 0.00 AC: 0 AN: 30970

American (AMR) AF: 0.0000300 AC: 1 AN: 33326

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22106

East Asian (EAS) AF: 0.00 AC: 0 AN: 39256

South Asian (SAS) AF: 0.00 AC: 0 AN: 77234

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50450

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5446

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1088236

Other (OTH) AF: 0.00 AC: 0 AN: 57846

GnomAD4 genome Cov.: 35

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Koolen-de Vries syndrome Uncertain:1

Apr 07, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not specified Benign:1

Aug 04, 2015

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.078	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	21
DANN	Benign	0.90
Eigen	Benign	-0.21
Eigen_PC	Benign	0.028
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.74	T
M_CAP	Benign	0.0051	T
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-0.96	T
PhyloP100		2.1
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-0.32	N
REVEL	Benign	0.17
Sift	Benign	0.28	T
Sift4G	Benign	0.22	T
Vest4		0.57
MutPred		0.098		Gain of glycosylation at S165 (P = 0.0507)
MVP		0.50
MPC		0.019
ClinPred		0.11	T
GERP RS		5.0
PromoterAI		0.021	Neutral
gMVP		0.16
Mutation Taster		=90/10	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: rs779594202; hg19: chr17-44249010;