NM_015443.4:c.*640T>C

Variant names:

• chr17-46030836-A-G
• rs17574361
• NM_015443.4:c.*640T>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.*640T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.143 in 152,604 control chromosomes in the GnomAD database, including 2,129 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.14 (2123 hom., cov: 31)
  • Exomes 𝑓: 0.14 (6 hom.)
• Consequence: KANSL1 NM_015443.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.69
• Publications: 40 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 17-46030836-A-G is Benign according to our data. Variant chr17-46030836-A-G is described in ClinVar as Benign. ClinVar VariationId is 323752.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.214 is higher than 0.05.

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.*640T>C		3_prime_UTR	Exon 15 of 15	NP_056258.1	Q7Z3B3-1
	KANSL1	NM_001193466.2		c.*640T>C		3_prime_UTR	Exon 15 of 15	NP_001180395.1	Q7Z3B3-1
	KANSL1	NM_001379198.1		c.*640T>C		3_prime_UTR	Exon 16 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.*640T>C		3_prime_UTR	Exon 15 of 15	ENSP00000387393.3	Q7Z3B3-1
	KANSL1	ENST00000262419.10	TSL:1	c.*640T>C		3_prime_UTR	Exon 15 of 15	ENSP00000262419.6	Q7Z3B3-1
	KANSL1	ENST00000572218.5	TSL:1	n.8175T>C		non_coding_transcript_exon	Exon 8 of 8

Frequencies

GnomAD3 genomes AF: 0.143 AC: 21778 AN: 152006 Hom.: 2125 Cov.: 31

Gnomad AFR AF: 0.0429

Gnomad AMI AF: 0.275

Gnomad AMR AF: 0.176

Gnomad ASJ AF: 0.240

Gnomad EAS AF: 0.00154

Gnomad SAS AF: 0.0740

Gnomad FIN AF: 0.0648

Gnomad MID AF: 0.218

Gnomad NFE AF: 0.217

Gnomad OTH AF: 0.183

GnomAD4 exome AF: 0.142 AC: 68 AN: 480 Hom.: 6 Cov.: 0 AF XY: 0.160 AC XY: 49 AN XY: 306

African (AFR) AC: 0 AN: 0

American (AMR) AF: 0.0769 AC: 2 AN: 26

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2

East Asian (EAS) AF: 0.00 AC: 0 AN: 8

South Asian (SAS) AF: 0.00 AC: 0 AN: 10

European-Finnish (FIN) AF: 0.190 AC: 8 AN: 42

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2

European-Non Finnish (NFE) AF: 0.155 AC: 55 AN: 354

Other (OTH) AF: 0.0833 AC: 3 AN: 36

GnomAD4 genome AF: 0.143 AC: 21767 AN: 152124 Hom.: 2123 Cov.: 31 AF XY: 0.134 AC XY: 9965 AN XY: 74374

African (AFR) AF: 0.0428 AC: 1779 AN: 41528

American (AMR) AF: 0.175 AC: 2679 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.240 AC: 830 AN: 3464

East Asian (EAS) AF: 0.00155 AC: 8 AN: 5172

South Asian (SAS) AF: 0.0740 AC: 357 AN: 4822

European-Finnish (FIN) AF: 0.0648 AC: 687 AN: 10596

Middle Eastern (MID) AF: 0.214 AC: 63 AN: 294

European-Non Finnish (NFE) AF: 0.217 AC: 14735 AN: 67962

Other (OTH) AF: 0.180 AC: 379 AN: 2102

Alfa AF: 0.199 Hom.: 4372

Bravo AF: 0.148

Asia WGS AF: 0.0310 AC: 109 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	MAPT-Related Spectrum Disorders (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	8.3
DANN	Benign	0.76
PhyloP100		1.7
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: rs17574361; hg19: chr17-44108202;