Genetic Variant KDM1A:p.Asp580Gly (chr1-23077232-A-G) – ACMG Classification: Likely_pathogenic (8 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM1PM2PP3_ModeratePP5_Moderate

The NM_001009999.3(KDM1A):c.1739A>G(p.Asp580Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. D580D) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Consequence

KDM1A
NM_001009999.3 missense

Scores

Clinical Significance

Pathogenic criteria provided, single submitter P:1U:1

Conservation

PhyloP100: 9.30

Publications

11 publications found

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 Gene-Disease associations (from GenCC):

palatal anomalies-widely spaced teeth-facial dysmorphism-developmental delay syndrome
Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae)

KDM1A links:

ENSG00000240553 (HGNC:):

ENSG00000240553 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_001009999.3

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.881

PP5

Variant 1-23077232-A-G is Pathogenic according to our data. Variant chr1-23077232-A-G is described in ClinVar as Pathogenic. ClinVar VariationId is 218913.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001009999.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
KDM1A	NM_001009999.3	MANE Select	c.1739A>G	p.Asp580Gly	missense	Exon 16 of 21	NP_001009999.1
KDM1A	NM_001410762.1		c.1745A>G	p.Asp582Gly	missense	Exon 15 of 20	NP_001397691.1
KDM1A	NM_001363654.2		c.1685A>G	p.Asp562Gly	missense	Exon 14 of 19	NP_001350583.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
KDM1A	ENST00000400181.9	TSL:1 MANE Select	c.1739A>G	p.Asp580Gly	missense	Exon 16 of 21	ENSP00000383042.5
KDM1A	ENST00000356634.7	TSL:1	c.1667A>G	p.Asp556Gly	missense	Exon 14 of 19	ENSP00000349049.3
KDM1A	ENST00000685102.1		c.1745A>G	p.Asp582Gly	missense	Exon 15 of 20	ENSP00000509257.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

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

Pathogenic:1Uncertain:1

Dec 10, 2015

OMIM

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:literature only

Sep 30, 2015

University of Washington Center for Mendelian Genomics, University of Washington

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.47

BayesDel_noAF

Pathogenic

0.44

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.75

Eigen

Pathogenic

0.81

Eigen_PC

Pathogenic

0.81

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.97

M_CAP

Uncertain

0.14

MetaRNN

Pathogenic

0.88

MetaSVM

Pathogenic

0.89

MutationAssessor

Uncertain

2.7

PhyloP100

9.3

PrimateAI

Pathogenic

0.90

PROVEAN

Pathogenic

-6.4

REVEL

Pathogenic

0.93

Sift

Uncertain

0.010

Sift4G

Uncertain

0.0070

Polyphen

1.0

Vest4

0.81

MutPred

0.63

Loss of stability (P = 0.0811)

MVP

0.93

MPC

3.0

ClinPred

0.99

GERP RS

5.7

PromoterAI

-0.031

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.91

gMVP

0.88

Mutation Taster

=1/99

disease causing (ClinVar)

(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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over