chr1-23019652-C-G

Variant names:

• chr1-23019652-C-G
• rs1241993370
• NM_001009999.3:c.56C>G

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001009999.3(KDM1A):​c.56C>G​(p.Thr19Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000426 in 1,409,208 control chromosomes in the GnomAD database, with no homozygous occurrence. There is a variant allele frequency bias in the population database for this variant (GnomAdExome4), which may indicate mosaicism or somatic mutations in the reference population data. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. T19T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000040 (0 hom.)
• Consequence: KDM1A NM_001009999.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.00100
• 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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.05338508).

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.56C>G	p.Thr19Ser	missense	Exon 1 of 21	NP_001009999.1	O60341-2
	KDM1A	NM_001410762.1		c.56C>G	p.Thr19Ser	missense	Exon 1 of 20	NP_001397691.1	A0A8I5KXU4
	KDM1A	NM_001363654.2		c.56C>G	p.Thr19Ser	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.56C>G	p.Thr19Ser	missense	Exon 1 of 21	ENSP00000383042.5	O60341-2
	KDM1A	ENST00000356634.7	TSL:1	c.56C>G	p.Thr19Ser	missense	Exon 1 of 19	ENSP00000349049.3	O60341-1
	KDM1A	ENST00000874661.1		c.56C>G	p.Thr19Ser	missense	Exon 1 of 21	ENSP00000544720.1

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152084 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000398 AC: 5 AN: 1257124 Hom.: 0 Cov.: 31 AF XY: 0.00000486 AC XY: 3 AN XY: 617468

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 25188

American (AMR) AF: 0.00 AC: 0 AN: 16190

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19786

East Asian (EAS) AF: 0.00 AC: 0 AN: 28492

South Asian (SAS) AF: 0.00 AC: 0 AN: 60052

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 31452

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3620

European-Non Finnish (NFE) AF: 0.00000490 AC: 5 AN: 1020748

Other (OTH) AF: 0.00 AC: 0 AN: 51596

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0182349), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 152084 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74288

African (AFR) AF: 0.00 AC: 0 AN: 41432

American (AMR) AF: 0.00 AC: 0 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10592

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67974

Other (OTH) AF: 0.00 AC: 0 AN: 2094

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	0.065
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	15
DANN	Benign	0.94
DEOGEN2	Benign	0.094	T
Eigen	Benign	-0.63
Eigen_PC	Benign	-0.51
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.40	T
M_CAP	Benign	0.080	D
MetaRNN	Benign	0.053	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.34	N
PhyloP100		0.0010
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	0.050	N
REVEL	Benign	0.056
Sift	Benign	0.19	T
Sift4G	Benign	0.97	T
Polyphen		0.0	B
Vest4		0.10
MutPred		0.11		Loss of catalytic residue at T19 (P = 0.1896)
MVP		0.17
MPC		1.0
ClinPred		0.28	T
GERP RS		3.6
PromoterAI		-0.055	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.089
gMVP		0.098
Mutation Taster		=94/6	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

dbSNP: rs1241993370; hg19: chr1-23346145;