chr9-137817423-ACT-A

Variant names:

• chr9-137817423-ACT-A
• rs112664025
• NM_024757.5:c.3375-11_3375-10delCT

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_024757.5(EHMT1):​c.3375-11_3375-10delCT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0589 in 1,613,552 control chromosomes in the GnomAD database, including 3,276 homozygotes. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.052 (241 hom., cov: 32)
  • Exomes 𝑓: 0.060 (3035 hom.)
• Consequence: EHMT1 NM_024757.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.0480
• Publications: 0 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 -16 ACMG points.

• BP6: Variant 9-137817423-ACT-A is Benign according to our data. Variant chr9-137817423-ACT-A is described in ClinVar as Benign. ClinVar VariationId is 96154.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.112 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EHMT1	NM_024757.5	MANE Select	c.3375-11_3375-10delCT		intron	N/A	NP_079033.4
	EHMT1	NM_001354263.2		c.3354-11_3354-10delCT		intron	N/A	NP_001341192.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EHMT1	ENST00000460843.6	TSL:5 MANE Select	c.3375-11_3375-10delCT		intron	N/A	ENSP00000417980.1
	EHMT1	ENST00000475564.5	TSL:1	n.1088_1089delCT		non_coding_transcript_exon	Exon 1 of 4
	EHMT1	ENST00000494249.5	TSL:1	n.728-11_728-10delCT		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0515 AC: 7821 AN: 151730 Hom.: 236 Cov.: 32

Gnomad AFR AF: 0.0480

Gnomad AMI AF: 0.137

Gnomad AMR AF: 0.0308

Gnomad ASJ AF: 0.0283

Gnomad EAS AF: 0.00174

Gnomad SAS AF: 0.120

Gnomad FIN AF: 0.0436

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.0588

Gnomad OTH AF: 0.0489

GnomAD2 exomes AF: 0.0549 AC: 13758 AN: 250808 AF XY: 0.0594

Gnomad AFR exome AF: 0.0488

Gnomad AMR exome AF: 0.0221

Gnomad ASJ exome AF: 0.0338

Gnomad EAS exome AF: 0.000707

Gnomad FIN exome AF: 0.0469

Gnomad NFE exome AF: 0.0606

Gnomad OTH exome AF: 0.0498

GnomAD4 exome AF: 0.0596 AC: 87168 AN: 1461704 Hom.: 3035 AF XY: 0.0617 AC XY: 44884 AN XY: 727178

African (AFR) AF: 0.0451 AC: 1511 AN: 33478

American (AMR) AF: 0.0226 AC: 1013 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0339 AC: 886 AN: 26134

East Asian (EAS) AF: 0.000327 AC: 13 AN: 39700

South Asian (SAS) AF: 0.119 AC: 10239 AN: 86254

European-Finnish (FIN) AF: 0.0466 AC: 2483 AN: 53336

Middle Eastern (MID) AF: 0.0426 AC: 246 AN: 5768

European-Non Finnish (NFE) AF: 0.0605 AC: 67318 AN: 1111920

Other (OTH) AF: 0.0573 AC: 3459 AN: 60390

GnomAD4 genome AF: 0.0516 AC: 7840 AN: 151848 Hom.: 241 Cov.: 32 AF XY: 0.0514 AC XY: 3813 AN XY: 74194

African (AFR) AF: 0.0483 AC: 1999 AN: 41416

American (AMR) AF: 0.0306 AC: 467 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.0283 AC: 98 AN: 3468

East Asian (EAS) AF: 0.00175 AC: 9 AN: 5146

South Asian (SAS) AF: 0.120 AC: 576 AN: 4800

European-Finnish (FIN) AF: 0.0436 AC: 459 AN: 10536

Middle Eastern (MID) AF: 0.0340 AC: 10 AN: 294

European-Non Finnish (NFE) AF: 0.0588 AC: 3990 AN: 67902

Other (OTH) AF: 0.0512 AC: 108 AN: 2108

Alfa AF: 0.0508 Hom.: 43

Bravo AF: 0.0484

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not specified (2)
-	-	1	Kleefstra syndrome 1 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.048
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs112664025; hg19: chr9-140711875;