rs1078997

Variant names:

• chr17-46032477-A-G
• rs1078997
• NM_015443.4:c.2838-178T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_015443.4(KANSL1):​c.2838-178T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.161 in 501,908 control chromosomes in the GnomAD database, including 7,952 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.15 (1918 hom., cov: 32)
  • Exomes 𝑓: 0.17 (6034 hom.)
• Consequence: KANSL1 NM_015443.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.257
• Publications: 10 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 17-46032477-A-G is Benign according to our data. Variant chr17-46032477-A-G is described in ClinVar as Benign. ClinVar VariationId is 1244049.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.446 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KANSL1	NM_015443.4	c.2838-178T>C		intron_variant	Intron 13 of 14	ENST00000432791.7	NP_056258.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KANSL1	ENST00000432791.7	c.2838-178T>C		intron_variant	Intron 13 of 14	1	NM_015443.4	ENSP00000387393.3

Frequencies

GnomAD3 genomes AF: 0.145 AC: 22036 AN: 151974 Hom.: 1909 Cov.: 32

Gnomad AFR AF: 0.0826

Gnomad AMI AF: 0.183

Gnomad AMR AF: 0.190

Gnomad ASJ AF: 0.130

Gnomad EAS AF: 0.461

Gnomad SAS AF: 0.168

Gnomad FIN AF: 0.136

Gnomad MID AF: 0.269

Gnomad NFE AF: 0.148

Gnomad OTH AF: 0.163

GnomAD4 exome AF: 0.167 AC: 58577 AN: 349816 Hom.: 6034 Cov.: 5 AF XY: 0.167 AC XY: 30094 AN XY: 179884

African (AFR) AF: 0.0839 AC: 817 AN: 9738

American (AMR) AF: 0.167 AC: 2001 AN: 11948

Ashkenazi Jewish (ASJ) AF: 0.137 AC: 1544 AN: 11258

East Asian (EAS) AF: 0.413 AC: 10843 AN: 26266

South Asian (SAS) AF: 0.176 AC: 3327 AN: 18904

European-Finnish (FIN) AF: 0.136 AC: 3396 AN: 24888

Middle Eastern (MID) AF: 0.229 AC: 400 AN: 1748

European-Non Finnish (NFE) AF: 0.147 AC: 32778 AN: 223580

Other (OTH) AF: 0.162 AC: 3471 AN: 21486

GnomAD4 genome AF: 0.145 AC: 22065 AN: 152092 Hom.: 1918 Cov.: 32 AF XY: 0.149 AC XY: 11043 AN XY: 74350

African (AFR) AF: 0.0828 AC: 3434 AN: 41484

American (AMR) AF: 0.190 AC: 2900 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.130 AC: 453 AN: 3472

East Asian (EAS) AF: 0.461 AC: 2378 AN: 5156

South Asian (SAS) AF: 0.169 AC: 813 AN: 4814

European-Finnish (FIN) AF: 0.136 AC: 1439 AN: 10586

Middle Eastern (MID) AF: 0.272 AC: 80 AN: 294

European-Non Finnish (NFE) AF: 0.148 AC: 10041 AN: 67976

Other (OTH) AF: 0.170 AC: 360 AN: 2112

Alfa AF: 0.146 Hom.: 5043

Bravo AF: 0.144

Asia WGS AF: 0.330 AC: 1147 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 23, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.097
DANN	Benign	0.73
PhyloP100		0.26
Mutation Taster		=100/0	polymorphism (auto)

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: rs1078997; hg19: chr17-44109843;