rs864309715

Variant names:

• chr1-23068566-G-A
• rs864309715
• NM_001009999.3:c.1207G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM2 PM5 PP3_Moderate PP5_Moderate

The NM_001009999.3(KDM1A):​c.1207G>A​(p.Glu403Lys) 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E403A) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: KDM1A NM_001009999.3 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 9.97
• Publications: 15 publications found

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)

ENSG00000240553 (HGNC:):

ACMG classification

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

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-23068567-A-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 1691768.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.876
• PP5: Variant 1-23068566-G-A is Pathogenic according to our data. Variant chr1-23068566-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 218912.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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KDM1A	NM_001009999.3	MANE Select	c.1207G>A	p.Glu403Lys	missense	Exon 11 of 21	NP_001009999.1
	KDM1A	NM_001410762.1		c.1195G>A	p.Glu399Lys	missense	Exon 10 of 20	NP_001397691.1
	KDM1A	NM_001363654.2		c.1135G>A	p.Glu379Lys	missense	Exon 9 of 19	NP_001350583.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KDM1A	ENST00000400181.9	TSL:1 MANE Select	c.1207G>A	p.Glu403Lys	missense	Exon 11 of 21	ENSP00000383042.5
	KDM1A	ENST00000356634.7	TSL:1	c.1135G>A	p.Glu379Lys	missense	Exon 9 of 19	ENSP00000349049.3
	KDM1A	ENST00000874661.1		c.1195G>A	p.Glu399Lys	missense	Exon 10 of 21	ENSP00000544720.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
2	-	-	Palatal anomalies-widely spaced teeth-facial dysmorphism-developmental delay syndrome (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.45
CADD	Pathogenic	31
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.76	D
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.97
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.23	D
MetaRNN	Pathogenic	0.88	D
MetaSVM	Pathogenic	0.94	D
MutationAssessor	Uncertain	2.6	M
PhyloP100		10
PrimateAI	Pathogenic	0.87	D
PROVEAN	Uncertain	-3.5	D
REVEL	Pathogenic	0.86
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0050	D
Polyphen		1.0	D
Vest4		0.86
MutPred		0.56		Gain of methylation at E379 (P = 0.0101)
MVP		0.97
MPC		2.8
ClinPred		0.96	D
GERP RS		5.8
Varity_R		0.90
gMVP		0.98
Mutation Taster		=7/93	disease causing (ClinVar)

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: rs864309715; hg19: chr1-23395059; COSMIC: COSV63086495;