dbSNP rs142062936: KANSL1:p.Pro429Thr (chr17-46170859-G-T) – ACMG Classification: Benign (-18 pts)

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_ModerateBP6_Very_StrongBS1BS2

The NM_015443.4(KANSL1):c.1285C>A(p.Pro429Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000805 in 1,602,262 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00043 ( 1 hom., cov: 35)

Exomes 𝑓: 0.000044 ( 0 hom. )

Consequence

KANSL1
NM_015443.4 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 4.77

Publications

1 publications found

Variant links:

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

KANSL1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -18 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.06887427).

BP6

Variant 17-46170859-G-T is Benign according to our data. Variant chr17-46170859-G-T is described in ClinVar as Likely_benign. ClinVar VariationId is 205787.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000427 (65/152296) while in subpopulation AFR AF = 0.00149 (62/41546). AF 95% confidence interval is 0.00119. There are 1 homozygotes in GnomAd4. There are 34 alleles in the male GnomAd4 subpopulation. Median coverage is 35. This position passed quality control check.

BS2

High AC in GnomAd4 at 65 AD gene.

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
KANSL1	NM_015443.4	MANE Select	c.1285C>A	p.Pro429Thr	missense	Exon 2 of 15	NP_056258.1	Q7Z3B3-1
KANSL1	NM_001193466.2		c.1285C>A	p.Pro429Thr	missense	Exon 2 of 15	NP_001180395.1	Q7Z3B3-1
KANSL1	NM_001379198.1		c.1285C>A	p.Pro429Thr	missense	Exon 3 of 16	NP_001366127.1	Q7Z3B3-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
KANSL1	ENST00000432791.7	TSL:1 MANE Select	c.1285C>A	p.Pro429Thr	missense	Exon 2 of 15	ENSP00000387393.3	Q7Z3B3-1
KANSL1	ENST00000262419.10	TSL:1	c.1285C>A	p.Pro429Thr	missense	Exon 2 of 15	ENSP00000262419.6	Q7Z3B3-1
KANSL1	ENST00000918919.1		c.1285C>A	p.Pro429Thr	missense	Exon 2 of 16	ENSP00000588978.1

Frequencies

GnomAD3 genomes

AF:

0.000427

AC:

AN:

152178

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00150

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.0000697

AC:

AN:

243898

AF XY:

0.0000607

show subpopulations

Gnomad AFR exome

AF:

0.000930

Gnomad AMR exome

AF:

0.0000303

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000900

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000441

AC:

AN:

1449966

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

720150

show subpopulations

African (AFR)

AF:

0.00176

AC:

AN:

32970

American (AMR)

AF:

0.0000466

AC:

AN:

42960

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25534

East Asian (EAS)

AF:

0.00

AC:

AN:

39404

South Asian (SAS)

AF:

0.00

AC:

AN:

85214

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52486

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5702

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1105890

Other (OTH)

AF:

0.0000669

AC:

AN:

59806

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.460

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000427

AC:

AN:

152296

Hom.:

Cov.:

AF XY:

0.000457

AC XY:

AN XY:

74458

show subpopulations

African (AFR)

AF:

0.00149

AC:

AN:

41546

American (AMR)

AF:

0.000131

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5174

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68036

Other (OTH)

AF:

0.000473

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000140

Hom.:

Bravo

AF:

0.000570

ESP6500AA

AF:

0.00113

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000988

AC:

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Koolen-de Vries syndrome (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.35

CADD

Benign

(source)

DANN

Uncertain

1.0

Eigen

Uncertain

0.56

Eigen_PC

Uncertain

0.53

FATHMM_MKL

Uncertain

0.88

LIST_S2

Uncertain

0.88

M_CAP

Benign

0.024

MetaRNN

Benign

0.069

MetaSVM

Benign

-1.1

PhyloP100

4.8

PrimateAI

Uncertain

0.56

PROVEAN

Uncertain

-3.8

REVEL

Benign

0.15

Sift

Uncertain

0.0070

Sift4G

Uncertain

0.020

Vest4

0.62

MVP

0.24

MPC

0.060

ClinPred

0.11

GERP RS

4.3

gMVP

0.25

Mutation Taster

=84/16

polymorphism

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over