NM_024757.5:c.1089T>C

Variant names:

• chr9-137744009-T-C
• rs1129768
• NM_024757.5:c.1089T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_024757.5(EHMT1):​c.1089T>C​(p.Gly363Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.377 in 1,613,856 control chromosomes in the GnomAD database, including 125,574 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.49 (21318 hom., cov: 33)
  • Exomes 𝑓: 0.37 (104256 hom.)
• Consequence: EHMT1 NM_024757.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -1.02
• Publications: 19 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 9-137744009-T-C is Benign according to our data. Variant chr9-137744009-T-C is described in ClinVar as Benign. ClinVar VariationId is 65724.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.02 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.79 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.1089T>C	p.Gly363Gly	synonymous	Exon 6 of 27	NP_079033.4
	EHMT1	NM_001354263.2		c.1068T>C	p.Gly356Gly	synonymous	Exon 6 of 27	NP_001341192.1
	EHMT1	NM_001354259.2		c.996T>C	p.Gly332Gly	synonymous	Exon 5 of 16	NP_001341188.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EHMT1	ENST00000460843.6	TSL:5 MANE Select	c.1089T>C	p.Gly363Gly	synonymous	Exon 6 of 27	ENSP00000417980.1
	EHMT1	ENST00000462484.5	TSL:1	c.1089T>C	p.Gly363Gly	synonymous	Exon 6 of 16	ENSP00000417328.1
	EHMT1	ENST00000896765.1		c.1161T>C	p.Gly387Gly	synonymous	Exon 7 of 28	ENSP00000566824.1

Frequencies

GnomAD3 genomes AF: 0.486 AC: 73917 AN: 151962 Hom.: 21278 Cov.: 33

Gnomad AFR AF: 0.797

Gnomad AMI AF: 0.405

Gnomad AMR AF: 0.536

Gnomad ASJ AF: 0.430

Gnomad EAS AF: 0.123

Gnomad SAS AF: 0.356

Gnomad FIN AF: 0.283

Gnomad MID AF: 0.472

Gnomad NFE AF: 0.359

Gnomad OTH AF: 0.481

GnomAD2 exomes AF: 0.395 AC: 99134 AN: 251076 AF XY: 0.382

Gnomad AFR exome AF: 0.805

Gnomad AMR exome AF: 0.572

Gnomad ASJ exome AF: 0.434

Gnomad EAS exome AF: 0.116

Gnomad FIN exome AF: 0.277

Gnomad NFE exome AF: 0.355

Gnomad OTH exome AF: 0.395

GnomAD4 exome AF: 0.365 AC: 534023 AN: 1461776 Hom.: 104256 Cov.: 61 AF XY: 0.365 AC XY: 265084 AN XY: 727184

African (AFR) AF: 0.817 AC: 27353 AN: 33480

American (AMR) AF: 0.567 AC: 25339 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.436 AC: 11394 AN: 26136

East Asian (EAS) AF: 0.131 AC: 5209 AN: 39700

South Asian (SAS) AF: 0.367 AC: 31653 AN: 86254

European-Finnish (FIN) AF: 0.282 AC: 15011 AN: 53324

Middle Eastern (MID) AF: 0.440 AC: 2538 AN: 5768

European-Non Finnish (NFE) AF: 0.353 AC: 392464 AN: 1111996

Other (OTH) AF: 0.382 AC: 23062 AN: 60396

GnomAD4 genome AF: 0.487 AC: 74016 AN: 152080 Hom.: 21318 Cov.: 33 AF XY: 0.482 AC XY: 35861 AN XY: 74340

African (AFR) AF: 0.797 AC: 33095 AN: 41502

American (AMR) AF: 0.536 AC: 8194 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.430 AC: 1491 AN: 3468

East Asian (EAS) AF: 0.124 AC: 640 AN: 5164

South Asian (SAS) AF: 0.357 AC: 1723 AN: 4824

European-Finnish (FIN) AF: 0.283 AC: 2995 AN: 10566

Middle Eastern (MID) AF: 0.473 AC: 139 AN: 294

European-Non Finnish (NFE) AF: 0.359 AC: 24368 AN: 67962

Other (OTH) AF: 0.476 AC: 1002 AN: 2106

Alfa AF: 0.402 Hom.: 7050

Bravo AF: 0.519

Asia WGS AF: 0.251 AC: 877 AN: 3478

EpiCase AF: 0.371

EpiControl AF: 0.362

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	2	Kleefstra syndrome 1 (2)
-	-	2	not provided (2)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.086
DANN	Benign	0.35
PhyloP100		-1.0
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.7
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: rs1129768; hg19: chr9-140638461; COSMIC: COSV58375109; COSMIC: COSV58375109;