NM_024757.5:c.3000C>T

Variant names:

• chr9-137813138-C-T
• rs35943616
• NM_024757.5:c.3000C>T

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.3000C>T​(p.Pro1000Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0184 in 1,611,890 control chromosomes in the GnomAD database, including 4,507 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.097 (2380 hom., cov: 33)
  • Exomes 𝑓: 0.010 (2127 hom.)
• Consequence: EHMT1 NM_024757.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -4.12
• Publications: 6 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: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 9-137813138-C-T is Benign according to our data. Variant chr9-137813138-C-T is described in ClinVar as Benign. ClinVar VariationId is 96151.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-4.12 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.332 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.3000C>T	p.Pro1000Pro	synonymous	Exon 20 of 27	NP_079033.4
	EHMT1	NM_001354263.2		c.2979C>T	p.Pro993Pro	synonymous	Exon 20 of 27	NP_001341192.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EHMT1	ENST00000460843.6	TSL:5 MANE Select	c.3000C>T	p.Pro1000Pro	synonymous	Exon 20 of 27	ENSP00000417980.1	Q9H9B1-1
	EHMT1	ENST00000918863.1		c.2878C>T	p.Arg960*	stop_gained	Exon 19 of 26	ENSP00000588922.1
	EHMT1	ENST00000896765.1		c.3072C>T	p.Pro1024Pro	synonymous	Exon 21 of 28	ENSP00000566824.1

Frequencies

GnomAD3 genomes AF: 0.0970 AC: 14756 AN: 152078 Hom.: 2368 Cov.: 33

Gnomad AFR AF: 0.336

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0377

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00347

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.00101

Gnomad OTH AF: 0.0789

GnomAD2 exomes AF: 0.0258 AC: 6434 AN: 249276 AF XY: 0.0187

Gnomad AFR exome AF: 0.343

Gnomad AMR exome AF: 0.0176

Gnomad ASJ exome AF: 0.00119

Gnomad EAS exome AF: 0.00315

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000978

Gnomad OTH exome AF: 0.0137

GnomAD4 exome AF: 0.0101 AC: 14785 AN: 1459694 Hom.: 2127 Cov.: 32 AF XY: 0.00859 AC XY: 6241 AN XY: 726298

African (AFR) AF: 0.347 AC: 11619 AN: 33478

American (AMR) AF: 0.0193 AC: 864 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00157 AC: 41 AN: 26136

East Asian (EAS) AF: 0.00433 AC: 172 AN: 39698

South Asian (SAS) AF: 0.000522 AC: 45 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51284

Middle Eastern (MID) AF: 0.0130 AC: 75 AN: 5766

European-Non Finnish (NFE) AF: 0.000579 AC: 644 AN: 1111982

Other (OTH) AF: 0.0219 AC: 1325 AN: 60374

GnomAD4 genome AF: 0.0973 AC: 14810 AN: 152196 Hom.: 2380 Cov.: 33 AF XY: 0.0929 AC XY: 6913 AN XY: 74422

African (AFR) AF: 0.337 AC: 13963 AN: 41476

American (AMR) AF: 0.0376 AC: 575 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00173 AC: 6 AN: 3472

East Asian (EAS) AF: 0.00348 AC: 18 AN: 5172

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.0306 AC: 9 AN: 294

European-Non Finnish (NFE) AF: 0.00101 AC: 69 AN: 68016

Other (OTH) AF: 0.0781 AC: 165 AN: 2112

Alfa AF: 0.0435 Hom.: 628

Bravo AF: 0.112

Asia WGS AF: 0.0210 AC: 74 AN: 3478

EpiCase AF: 0.00131

EpiControl AF: 0.00136

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	0.16
DANN	Benign	0.49
PhyloP100		-4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs35943616; hg19: chr9-140707590; COSMIC: COSV107533394; COSMIC: COSV107533394;