Genetic Variant KDM1A:p.Ala10Val (chr1-23019625-C-T) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_001009999.3(KDM1A):c.29C>T(p.Ala10Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000571 in 1,225,804 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. A10A) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000057 ( 0 hom. )

Consequence

KDM1A
NM_001009999.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.77

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:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.1801439).

BS2

High AC in GnomAdExome4 at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KDM1A	NM_001009999.3 link	c.29C>T	p.Ala10Val	missense_variant	Exon 1 of 21	ENST00000400181.9	NP_001009999.1	O60341-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KDM1A	ENST00000400181.9 link	c.29C>T	p.Ala10Val	missense_variant	Exon 1 of 21	1	NM_001009999.3	ENSP00000383042.5		O60341-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000374

AC:

AN:

53406

Hom.:

AF XY:

0.0000318

AC XY:

AN XY:

31492

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000111

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000383

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000571

AC:

AN:

1225804

Hom.:

Cov.:

AF XY:

0.0000100

AC XY:

AN XY:

600052

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000752

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.98e-7

Gnomad4 OTH exome

AF:

0.0000401

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ExAC

AF:

0.00000967

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Oct 20, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 10 of the KDM1A protein (p.Ala10Val). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with KDM1A-related conditions. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬†is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.26

BayesDel_addAF

Benign

-0.098

BayesDel_noAF

Benign

-0.38

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.11

.;T;.

Eigen

Benign

-0.0014

Eigen_PC

Benign

0.0080

FATHMM_MKL

Benign

0.11

LIST_S2

Benign

0.84

T;T;T

M_CAP

Uncertain

0.28

MetaRNN

Benign

0.18

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.0

.;N;N

PrimateAI

Pathogenic

0.88

PROVEAN

Benign

-0.090

.;N;N

REVEL

Benign

0.085

Sift

Pathogenic

0.0

.;D;D

Sift4G

Benign

0.40

.;T;T

Polyphen

0.96, 0.98

.;D;D

Vest4

0.35, 0.34

MutPred

0.38

Gain of catalytic residue at A10 (P = 0.0125);Gain of catalytic residue at A10 (P = 0.0125);Gain of catalytic residue at A10 (P = 0.0125);

MVP

0.42

MPC

1.1

ClinPred

0.29

GERP RS

4.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.6

Varity_R

0.30

gMVP

0.43

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