chr9-137700463-A-G

Variant names:

• chr9-137700463-A-G
• rs10780183
• NM_024757.5:c.22-10504A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_024757.5(EHMT1):​c.22-10504A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.18 in 152,216 control chromosomes in the GnomAD database, including 2,722 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.18 (2722 hom., cov: 32)
• Consequence: EHMT1 NM_024757.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.113
• Publications: 2 publications found

Genes affected

EHMT1 (HGNC:24650): (euchromatic histone lysine methyltransferase 1) The protein encoded by this gene is a histone methyltransferase that methylates the lysine-9 position of histone H3. This action marks the genomic region packaged with these methylated histones for transcriptional repression. This protein may be involved in the silencing of MYC- and E2F-responsive genes and therefore could play a role in the G0/G1 cell cycle transition. Defects in this gene are a cause of chromosome 9q subtelomeric deletion syndrome (9q-syndrome, also known as Kleefstra syndrome). Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2017]

EHMT1 Gene-Disease associations (from GenCC):

• Kleefstra syndrome

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• Kleefstra syndrome 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)

ENSG00000283411 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.304 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024757.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EHMT1	NM_024757.5	MANE Select	c.22-10504A>G		intron	N/A	NP_079033.4
	EHMT1	NM_001354263.2		c.22-10504A>G		intron	N/A	NP_001341192.1
	EHMT1	NM_001354259.2		c.-8-16163A>G		intron	N/A	NP_001341188.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EHMT1	ENST00000460843.6	TSL:5 MANE Select	c.22-10504A>G		intron	N/A	ENSP00000417980.1
	EHMT1	ENST00000462484.5	TSL:1	c.22-10504A>G		intron	N/A	ENSP00000417328.1
	EHMT1	ENST00000637161.1	TSL:5	c.-72-10504A>G		intron	N/A	ENSP00000490328.1

Frequencies

GnomAD3 genomes AF: 0.180 AC: 27388 AN: 152098 Hom.: 2713 Cov.: 32

Gnomad AFR AF: 0.149

Gnomad AMI AF: 0.273

Gnomad AMR AF: 0.311

Gnomad ASJ AF: 0.174

Gnomad EAS AF: 0.108

Gnomad SAS AF: 0.237

Gnomad FIN AF: 0.209

Gnomad MID AF: 0.0918

Gnomad NFE AF: 0.166

Gnomad OTH AF: 0.164

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.180 AC: 27422 AN: 152216 Hom.: 2722 Cov.: 32 AF XY: 0.185 AC XY: 13746 AN XY: 74410

African (AFR) AF: 0.149 AC: 6194 AN: 41528

American (AMR) AF: 0.312 AC: 4764 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.174 AC: 604 AN: 3470

East Asian (EAS) AF: 0.109 AC: 566 AN: 5188

South Asian (SAS) AF: 0.238 AC: 1148 AN: 4826

European-Finnish (FIN) AF: 0.209 AC: 2218 AN: 10590

Middle Eastern (MID) AF: 0.102 AC: 30 AN: 294

European-Non Finnish (NFE) AF: 0.166 AC: 11304 AN: 68018

Other (OTH) AF: 0.164 AC: 346 AN: 2116

Alfa AF: 0.171 Hom.: 1408

Bravo AF: 0.187

Asia WGS AF: 0.157 AC: 549 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.66
DANN	Benign	0.26
PhyloP100		0.11
Mutation Taster		=100/0	polymorphism (auto)

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: rs10780183; hg19: chr9-140594915;