rs864309715

Positions:

• chr1-23068566-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 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

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]

ENSG00000240553 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 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 id 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 id is 218912.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KDM1A	NM_001009999.3	c.1207G>A	p.Glu403Lys	missense_variant	11/21	ENST00000400181.9	NP_001009999.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KDM1A	ENST00000400181.9	c.1207G>A	p.Glu403Lys	missense_variant	11/21	1	NM_001009999.3	ENSP00000383042.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Palatal anomalies-widely spaced teeth-facial dysmorphism-developmental delay syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	University of Washington Center for Mendelian Genomics, University of Washington	Sep 30, 2015	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 10, 2015	- -

Computational scores

Source: dbNSFP v4.3

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;D;D
M_CAP	Uncertain	0.23	D
MetaRNN	Pathogenic	0.88	D;D;D
MetaSVM	Pathogenic	0.94	D
MutationAssessor	Uncertain	2.6	.;M;.
PrimateAI	Pathogenic	0.87	D
PROVEAN	Uncertain	-3.5	.;D;D
REVEL	Pathogenic	0.86
Sift	Uncertain	0.0020	.;D;D
Sift4G	Uncertain	0.0050	.;D;D
Polyphen		1.0, 1.0	.;D;D
Vest4		0.86, 0.91
MutPred		0.56		Gain of methylation at E379 (P = 0.0101);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

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

Other links and lift over

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