1-23019657-A-C

Position:

• chr1-23019657-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_001009999.3(KDM1A):​c.61A>C​(p.Thr21Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. T21T) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: KDM1A NM_001009999.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.226

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 Uncertain_significance. Variant got 1 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.07236159).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KDM1A	NM_001009999.3	c.61A>C	p.Thr21Pro	missense_variant	1/21	ENST00000400181.9	NP_001009999.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KDM1A	ENST00000400181.9	c.61A>C	p.Thr21Pro	missense_variant	1/21	1	NM_001009999.3	ENSP00000383042.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 22, 2024

The p.T21P variant (also known as c.61A>C), located in coding exon 1 of the KDM1A gene, results from an A to C substitution at nucleotide position 61. The threonine at codon 21 is replaced by proline, an amino acid with highly similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	17
DANN	Benign	0.93
DEOGEN2	Benign	0.096	.;T;.
Eigen	Benign	-0.85
Eigen_PC	Benign	-0.79
FATHMM_MKL	Benign	0.076	N
LIST_S2	Benign	0.54	T;T;T
M_CAP	Uncertain	0.27	D
MetaRNN	Benign	0.072	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	.;N;N
PrimateAI	Pathogenic	0.89	D
PROVEAN	Benign	-0.11	.;N;N
REVEL	Benign	0.050
Sift	Pathogenic	0.0	.;D;D
Sift4G	Benign	0.30	.;T;T
Polyphen		0.028, 0.048	.;B;B
Vest4		0.12, 0.19
MutPred		0.11		Loss of glycosylation at T21 (P = 0.0191);Loss of glycosylation at T21 (P = 0.0191);Loss of glycosylation at T21 (P = 0.0191);
MVP		0.32
MPC		1.4
ClinPred		0.34	T
GERP RS		-0.37
Varity_R		0.23
gMVP		0.19

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-23346150;