1-23019657-A-C

Variant names:

• chr1-23019657-A-C
• NM_001009999.3:c.61A>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 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. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T21K) has been classified as Uncertain significance.

• 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
• Publications: 0 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07236159).

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.61A>C	p.Thr21Pro	missense	Exon 1 of 21	NP_001009999.1	O60341-2
	KDM1A	NM_001410762.1		c.61A>C	p.Thr21Pro	missense	Exon 1 of 20	NP_001397691.1	A0A8I5KXU4
	KDM1A	NM_001363654.2		c.61A>C	p.Thr21Pro	missense	Exon 1 of 19	NP_001350583.1	R4GMQ1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KDM1A	ENST00000400181.9	TSL:1 MANE Select	c.61A>C	p.Thr21Pro	missense	Exon 1 of 21	ENSP00000383042.5	O60341-2
	KDM1A	ENST00000356634.7	TSL:1	c.61A>C	p.Thr21Pro	missense	Exon 1 of 19	ENSP00000349049.3	O60341-1
	KDM1A	ENST00000874661.1		c.61A>C	p.Thr21Pro	missense	Exon 1 of 21	ENSP00000544720.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

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
M_CAP	Uncertain	0.27	D
MetaRNN	Benign	0.072	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
PhyloP100		-0.23
PrimateAI	Pathogenic	0.89	D
PROVEAN	Benign	-0.11	N
REVEL	Benign	0.050
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.30	T
Polyphen		0.028	B
Vest4		0.12
MutPred		0.11		Loss of glycosylation at T21 (P = 0.0191)
MVP		0.32
MPC		1.4
ClinPred		0.34	T
GERP RS		-0.37
PromoterAI		0.036	Neutral
Varity_R		0.23
gMVP		0.19
Mutation Taster		=85/15	polymorphism

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

hg19: chr1-23346150;