NM_001009999.3:c.69T>C

Variant names:

• chr1-23019665-T-C
• NM_001009999.3:c.69T>C

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 2P and 7B. PM2 BP4_Strong BP6_Moderate BP7

The NM_001009999.3(KDM1A):​c.69T>C​(p.Ala23Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000805 in 1,241,600 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 8.1e-7 (0 hom.)
• Consequence: KDM1A NM_001009999.3 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.40
• 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 -5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.61).
• BP6: Variant 1-23019665-T-C is Benign according to our data. Variant chr1-23019665-T-C is described in ClinVar as Likely_benign. ClinVar VariationId is 3646651.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-1.4 with no splicing effect.

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.69T>C	p.Ala23Ala	synonymous	Exon 1 of 21	NP_001009999.1	O60341-2
	KDM1A	NM_001410762.1		c.69T>C	p.Ala23Ala	synonymous	Exon 1 of 20	NP_001397691.1	A0A8I5KXU4
	KDM1A	NM_001363654.2		c.69T>C	p.Ala23Ala	synonymous	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.69T>C	p.Ala23Ala	synonymous	Exon 1 of 21	ENSP00000383042.5	O60341-2
	KDM1A	ENST00000356634.7	TSL:1	c.69T>C	p.Ala23Ala	synonymous	Exon 1 of 19	ENSP00000349049.3	O60341-1
	KDM1A	ENST00000874661.1		c.69T>C	p.Ala23Ala	synonymous	Exon 1 of 21	ENSP00000544720.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 8.05e-7 AC: 1 AN: 1241600 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 608250

⚠️ 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: 24694

American (AMR) AF: 0.0000702 AC: 1 AN: 14244

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19018

East Asian (EAS) AF: 0.00 AC: 0 AN: 28060

South Asian (SAS) AF: 0.00 AC: 0 AN: 56972

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 31310

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3584

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1012802

Other (OTH) AF: 0.00 AC: 0 AN: 50916

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.61
CADD	Benign	7.6
DANN	Benign	0.61
PhyloP100		-1.4
PromoterAI		0.11	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7
Mutation Taster		=100/0	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: chr1-23346158;