chr1-23019623-CGCG-C

Variant names:

• chr1-23019623-CGCG-C
• rs765476443
• NM_001009999.3:c.39_41delGGC

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP3

The NM_001009999.3(KDM1A):​c.39_41delGGC​(p.Ala14del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00054 in 1,261,444 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. A13A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00054 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: KDM1A NM_001009999.3 disruptive_inframe_deletion
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.77
• 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 -1 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_001009999.3

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.39_41delGGC	p.Ala14del	disruptive_inframe_deletion	Exon 1 of 21	NP_001009999.1	O60341-2
	KDM1A	NM_001410762.1		c.39_41delGGC	p.Ala14del	disruptive_inframe_deletion	Exon 1 of 20	NP_001397691.1	A0A8I5KXU4
	KDM1A	NM_001363654.2		c.39_41delGGC	p.Ala14del	disruptive_inframe_deletion	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.39_41delGGC	p.Ala14del	disruptive_inframe_deletion	Exon 1 of 21	ENSP00000383042.5	O60341-2
	KDM1A	ENST00000356634.7	TSL:1	c.39_41delGGC	p.Ala14del	disruptive_inframe_deletion	Exon 1 of 19	ENSP00000349049.3	O60341-1
	KDM1A	ENST00000874661.1		c.39_41delGGC	p.Ala14del	disruptive_inframe_deletion	Exon 1 of 21	ENSP00000544720.1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 151708 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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00324 AC: 190 AN: 58636 AF XY: 0.00348

Gnomad AFR exome AF: 0.00120

Gnomad AMR exome AF: 0.00389

Gnomad ASJ exome AF: 0.00428

Gnomad EAS exome AF: 0.000334

Gnomad FIN exome AF: 0.00192

Gnomad NFE exome AF: 0.00284

Gnomad OTH exome AF: 0.00633

GnomAD4 exome AF: 0.000540 AC: 681 AN: 1261444 Hom.: 0 AF XY: 0.000668 AC XY: 414 AN XY: 620174

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

African (AFR) AF: 0.000157 AC: 4 AN: 25418

American (AMR) AF: 0.00233 AC: 40 AN: 17150

Ashkenazi Jewish (ASJ) AF: 0.00128 AC: 25 AN: 19600

East Asian (EAS) AF: 0.000102 AC: 3 AN: 29514

South Asian (SAS) AF: 0.00266 AC: 158 AN: 59448

European-Finnish (FIN) AF: 0.000869 AC: 27 AN: 31082

Middle Eastern (MID) AF: 0.00142 AC: 5 AN: 3524

European-Non Finnish (NFE) AF: 0.000372 AC: 381 AN: 1024090

Other (OTH) AF: 0.000736 AC: 38 AN: 51618

⚠️ 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 Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 151708 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74084

African (AFR) AF: 0.00 AC: 0 AN: 41380

American (AMR) AF: 0.00 AC: 0 AN: 15068

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10544

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67926

Other (OTH) AF: 0.00 AC: 0 AN: 2084

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.8
Mutation Taster		=76/24	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: rs765476443; hg19: chr1-23346116; COSMIC: COSV105270671; COSMIC: COSV105270671;