1-23082274-T-C

Position:

• chr1-23082274-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM2 PP2 PP3_Strong PP5_Moderate

The NM_001009999.3(KDM1A):​c.2353T>C​(p.Tyr785His) 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 (★).

• Frequency: Genomes: not found (cov: 30)
• Consequence: KDM1A NM_001009999.3 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 8.02

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 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.976
• PP5: Variant 1-23082274-T-C is Pathogenic according to our data. Variant chr1-23082274-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 218911.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.2353T>C	p.Tyr785His	missense_variant	20/21	ENST00000400181.9	NP_001009999.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KDM1A	ENST00000400181.9	c.2353T>C	p.Tyr785His	missense_variant	20/21	1	NM_001009999.3	ENSP00000383042.5

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 30

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	0.54	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.80	.;D;.;.
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.92
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D;D;D
M_CAP	Pathogenic	0.50	D
MetaRNN	Pathogenic	0.98	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.1	.;H;.;.
PrimateAI	Pathogenic	0.93	D
PROVEAN	Uncertain	-4.0	.;D;D;.
REVEL	Pathogenic	0.98
Sift	Pathogenic	0.0	.;D;D;.
Sift4G	Pathogenic	0.0010	.;D;D;D
Polyphen		1.0, 1.0	.;D;D;.
Vest4		0.93, 0.90
MutPred		0.89		.;Gain of disorder (P = 0.046);.;.;
MVP		0.98
MPC		3.0
ClinPred		1.0	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.88
gMVP		0.94

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: rs864309714; hg19: chr1-23408767;