1-23019732-G-A

Position:

chr1-23019732-G-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PP2BP4_StrongBP6BS2

The ENST00000400181.9(KDM1A):c.136G>A(p.Gly46Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00737 in 1,331,034 control chromosomes in the GnomAD database, including 50 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0059 ( 4 hom., cov: 32)

Exomes 𝑓: 0.0076 ( 46 hom. )

Consequence

KDM1A
ENST00000400181.9 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:4

Conservation

PhyloP100: 4.09

Variant links:

Genes affected

KDM1A (HGNC:29079): (lysine demethylase 1A) This gene encodes a nuclear protein containing a SWIRM domain, a FAD-binding motif, and an amine oxidase domain. This protein is a component of several histone deacetylase complexes, though it silences genes by functioning as a histone demethylase. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Apr 2009]

KDM1A links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), KDM1A. . Gene score misZ 4.6784 (greater than the threshold 3.09). Trascript score misZ 3.7869 (greater than threshold 3.09). GenCC has associacion of gene with palatal anomalies-widely spaced teeth-facial dysmorphism-developmental delay syndrome.

BP4

Computational evidence support a benign effect (MetaRNN=0.0029521585).

BP6

Variant 1-23019732-G-A is Benign according to our data. Variant chr1-23019732-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 931593.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=1, Likely_benign=2}.

BS2

High AC in GnomAd4 at 903 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KDM1A	NM_001009999.3 linkuse as main transcript	c.136G>A	p.Gly46Ser	missense_variant	1/21	ENST00000400181.9	NP_001009999.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KDM1A	ENST00000400181.9 linkuse as main transcript	c.136G>A	p.Gly46Ser	missense_variant	1/21	1	NM_001009999.3	ENSP00000383042		O60341-2

Frequencies

GnomAD3 genomes

AF:

0.00594

AC:

903

AN:

151978

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00140

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00930

Gnomad ASJ

AF:

0.0135

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00104

Gnomad FIN

AF:

0.00397

Gnomad MID

AF:

0.00321

Gnomad NFE

AF:

0.00874

Gnomad OTH

AF:

0.00670

GnomAD3 exomes

AF:

0.00412

AC:

AN:

6800

Hom.:

AF XY:

0.00423

AC XY:

AN XY:

3306

show subpopulations

Gnomad AFR exome

AF:

0.0294

Gnomad AMR exome

AF:

0.0172

Gnomad ASJ exome

AF:

0.167

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00332

Gnomad NFE exome

AF:

0.00877

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00756

AC:

8908

AN:

1178948

Hom.:

Cov.:

AF XY:

0.00752

AC XY:

4267

AN XY:

567056

show subpopulations

Gnomad4 AFR exome

AF:

0.000602

Gnomad4 AMR exome

AF:

0.00710

Gnomad4 ASJ exome

AF:

0.0167

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00185

Gnomad4 FIN exome

AF:

0.00534

Gnomad4 NFE exome

AF:

0.00820

Gnomad4 OTH exome

AF:

0.00610

GnomAD4 genome

AF:

0.00594

AC:

903

AN:

152086

Hom.:

Cov.:

AF XY:

0.00589

AC XY:

438

AN XY:

74360

show subpopulations

Gnomad4 AFR

AF:

0.00140

Gnomad4 AMR

AF:

0.00928

Gnomad4 ASJ

AF:

0.0135

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00104

Gnomad4 FIN

AF:

0.00397

Gnomad4 NFE

AF:

0.00875

Gnomad4 OTH

AF:

0.00664

Alfa

AF:

0.00752

Hom.:

Bravo

AF:

0.00569

ExAC

AF:

0.00171

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	KDM1A: PP2, BS2 -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

Palatal anomalies-widely spaced teeth-facial dysmorphism-developmental delay syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Aug 12, 2019

This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: PP3,BS2. -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jan 18, 2022

- -

KDM1A-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 27, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.082

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.36

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.11

.;T;.

Eigen

Uncertain

0.26

Eigen_PC

Uncertain

0.27

FATHMM_MKL

Benign

0.65

LIST_S2

Benign

0.78

T;T;T

MetaRNN

Benign

0.0030

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.20

.;N;N

MutationTaster

Benign

0.91

D;D;D

PrimateAI

Pathogenic

0.91

PROVEAN

Benign

-0.22

.;N;N

REVEL

Benign

0.15

Sift

Pathogenic

0.0

.;D;D

Sift4G

Benign

0.62

.;T;T

Polyphen

0.98, 0.99

.;D;D

Vest4

0.21, 0.24

MVP

0.38

MPC

1.2

ClinPred

0.17

GERP RS

3.8

RBP_binding_hub_radar

0.92

RBP_regulation_power_radar

2.6

Varity_R

0.23

gMVP

0.31

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over