17-46171730-A-C

Variant names:

• chr17-46171730-A-C
• rs17662889
• NM_015443.4:c.414T>G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6_Very_Strong BP7

The NM_015443.4(KANSL1):​c.414T>G​(p.Leu138Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.152 in 1,538,972 control chromosomes in the GnomAD database, including 3 homozygotes. There is a variant allele frequency bias in the population database for this variant (GnomAd4), which may indicate mosaicism or somatic mutations in the reference population data. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (0 hom., cov: 35)
  • Exomes 𝑓: 0.16 (3 hom.)
• Consequence: KANSL1 NM_015443.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.259
• Publications: 21 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: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.67).
• BP6: Variant 17-46171730-A-C is Benign according to our data. Variant chr17-46171730-A-C is described in ClinVar as Benign. ClinVar VariationId is 323796.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.259 with no splicing effect.

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.414T>G	p.Leu138Leu	synonymous	Exon 2 of 15	NP_056258.1	Q7Z3B3-1
	KANSL1	NM_001193466.2		c.414T>G	p.Leu138Leu	synonymous	Exon 2 of 15	NP_001180395.1	Q7Z3B3-1
	KANSL1	NM_001379198.1		c.414T>G	p.Leu138Leu	synonymous	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.414T>G	p.Leu138Leu	synonymous	Exon 2 of 15	ENSP00000387393.3	Q7Z3B3-1
	KANSL1	ENST00000262419.10	TSL:1	c.414T>G	p.Leu138Leu	synonymous	Exon 2 of 15	ENSP00000262419.6	Q7Z3B3-1
	KANSL1	ENST00000918919.1		c.414T>G	p.Leu138Leu	synonymous	Exon 2 of 16	ENSP00000588978.1

Frequencies

GnomAD3 genomes AF: 0.115 AC: 17218 AN: 150176 Hom.: 0 Cov.: 35

Gnomad AFR AF: 0.0346

Gnomad AMI AF: 0.248

Gnomad AMR AF: 0.142

Gnomad ASJ AF: 0.181

Gnomad EAS AF: 0.00115

Gnomad SAS AF: 0.0519

Gnomad FIN AF: 0.0576

Gnomad MID AF: 0.171

Gnomad NFE AF: 0.174

Gnomad OTH AF: 0.148

GnomAD2 exomes AF: 0.120 AC: 25993 AN: 216306 AF XY: 0.122

Gnomad AFR exome AF: 0.0323

Gnomad AMR exome AF: 0.111

Gnomad ASJ exome AF: 0.198

Gnomad EAS exome AF: 0.000657

Gnomad FIN exome AF: 0.0614

Gnomad NFE exome AF: 0.176

Gnomad OTH exome AF: 0.147

GnomAD4 exome AF: 0.156 AC: 215991 AN: 1388680 Hom.: 3 Cov.: 35 AF XY: 0.153 AC XY: 105613 AN XY: 688948

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

African (AFR) AF: 0.0295 AC: 926 AN: 31390

American (AMR) AF: 0.115 AC: 4151 AN: 36096

Ashkenazi Jewish (ASJ) AF: 0.194 AC: 4470 AN: 23058

East Asian (EAS) AF: 0.000839 AC: 33 AN: 39348

South Asian (SAS) AF: 0.0575 AC: 4570 AN: 79472

European-Finnish (FIN) AF: 0.0657 AC: 3377 AN: 51366

Middle Eastern (MID) AF: 0.151 AC: 823 AN: 5446

European-Non Finnish (NFE) AF: 0.178 AC: 189444 AN: 1065168

Other (OTH) AF: 0.143 AC: 8197 AN: 57336

⚠️ 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 AF: 0.114 AC: 17204 AN: 150292 Hom.: 0 Cov.: 35 AF XY: 0.107 AC XY: 7906 AN XY: 73564

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

African (AFR) AF: 0.0344 AC: 1427 AN: 41446

American (AMR) AF: 0.142 AC: 2138 AN: 15058

Ashkenazi Jewish (ASJ) AF: 0.181 AC: 614 AN: 3392

East Asian (EAS) AF: 0.00116 AC: 6 AN: 5186

South Asian (SAS) AF: 0.0516 AC: 246 AN: 4770

European-Finnish (FIN) AF: 0.0576 AC: 608 AN: 10562

Middle Eastern (MID) AF: 0.163 AC: 47 AN: 288

European-Non Finnish (NFE) AF: 0.174 AC: 11593 AN: 66626

Other (OTH) AF: 0.147 AC: 303 AN: 2068

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.156 Hom.: 1190

Asia WGS AF: 0.0250 AC: 87 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Koolen-de Vries syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
CADD	Benign	7.5
DANN	Benign	0.68
PhyloP100		0.26
PromoterAI		-0.0031	Neutral
Mutation Taster		=294/6	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: rs17662889; hg19: chr17-44249096; COSMIC: COSV52270827; COSMIC: COSV52270827;