rs12238423

Variant names:

• chr9-137796831-A-G
• rs12238423
• NM_024757.5:c.2506-1982A>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.2506-1982A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.338 in 151,272 control chromosomes in the GnomAD database, including 8,974 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 0.34 (8974 hom., cov: 30)
• Consequence: EHMT1 NM_024757.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -4.70
• Publications: 1 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)

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.08).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.425 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EHMT1	NM_024757.5	c.2506-1982A>G		intron_variant	Intron 16 of 26	ENST00000460843.6	NP_079033.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EHMT1	ENST00000460843.6	c.2506-1982A>G		intron_variant	Intron 16 of 26	5	NM_024757.5	ENSP00000417980.1

Frequencies

GnomAD3 genomes AF: 0.338 AC: 51073 AN: 151156 Hom.: 8950 Cov.: 30

Gnomad AFR AF: 0.389

Gnomad AMI AF: 0.377

Gnomad AMR AF: 0.433

Gnomad ASJ AF: 0.378

Gnomad EAS AF: 0.130

Gnomad SAS AF: 0.352

Gnomad FIN AF: 0.255

Gnomad MID AF: 0.373

Gnomad NFE AF: 0.311

Gnomad OTH AF: 0.336

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

GnomAD4 genome AF: 0.338 AC: 51155 AN: 151272 Hom.: 8974 Cov.: 30 AF XY: 0.338 AC XY: 24922 AN XY: 73842

African (AFR) AF: 0.390 AC: 16033 AN: 41148

American (AMR) AF: 0.433 AC: 6555 AN: 15122

Ashkenazi Jewish (ASJ) AF: 0.378 AC: 1308 AN: 3464

East Asian (EAS) AF: 0.130 AC: 668 AN: 5138

South Asian (SAS) AF: 0.352 AC: 1689 AN: 4796

European-Finnish (FIN) AF: 0.255 AC: 2655 AN: 10408

Middle Eastern (MID) AF: 0.371 AC: 109 AN: 294

European-Non Finnish (NFE) AF: 0.311 AC: 21091 AN: 67888

Other (OTH) AF: 0.335 AC: 704 AN: 2104

Alfa AF: 0.339 Hom.: 3836

Bravo AF: 0.354

Asia WGS AF: 0.239 AC: 835 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.1
CADD	Benign	0.34
DANN	Benign	0.082
PhyloP100		-4.7
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: rs12238423; hg19: chr9-140691283;