rs4876902

Variant names:

• chr9-137816151-C-T
• rs4876902
• NM_024757.5:c.3374+89C>T

Your query was ambiguous. Multiple possible variants found:

• chr9-137816151-C-T
• chr9-137816151-C-A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_024757.5(EHMT1):​c.3374+89C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.223 in 1,231,248 control chromosomes in the GnomAD database, including 33,284 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.21 (3775 hom., cov: 33)
  • Exomes 𝑓: 0.23 (29509 hom.)
• Consequence: EHMT1 NM_024757.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -3.16
• Publications: 16 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 9-137816151-C-T is Benign according to our data. Variant chr9-137816151-C-T is described in ClinVar as Benign. ClinVar VariationId is 1255100.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.346 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.3374+89C>T		intron	N/A	NP_079033.4
	EHMT1	NM_001354263.2		c.3353+89C>T		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.3374+89C>T		intron	N/A	ENSP00000417980.1	Q9H9B1-1
	EHMT1	ENST00000494249.5	TSL:1	n.727+89C>T		intron	N/A
	EHMT1	ENST00000896765.1		c.3446+89C>T		intron	N/A	ENSP00000566824.1

Frequencies

GnomAD3 genomes AF: 0.207 AC: 31554 AN: 152094 Hom.: 3771 Cov.: 33

Gnomad AFR AF: 0.121

Gnomad AMI AF: 0.320

Gnomad AMR AF: 0.353

Gnomad ASJ AF: 0.231

Gnomad EAS AF: 0.0941

Gnomad SAS AF: 0.296

Gnomad FIN AF: 0.212

Gnomad MID AF: 0.190

Gnomad NFE AF: 0.226

Gnomad OTH AF: 0.215

GnomAD4 exome AF: 0.225 AC: 242974 AN: 1079036 Hom.: 29509 Cov.: 14 AF XY: 0.228 AC XY: 124656 AN XY: 545994

African (AFR) AF: 0.119 AC: 3003 AN: 25254

American (AMR) AF: 0.445 AC: 15717 AN: 35346

Ashkenazi Jewish (ASJ) AF: 0.242 AC: 5614 AN: 23172

East Asian (EAS) AF: 0.0945 AC: 3239 AN: 34266

South Asian (SAS) AF: 0.299 AC: 21758 AN: 72652

European-Finnish (FIN) AF: 0.213 AC: 9761 AN: 45772

Middle Eastern (MID) AF: 0.200 AC: 986 AN: 4922

European-Non Finnish (NFE) AF: 0.218 AC: 172562 AN: 789962

Other (OTH) AF: 0.217 AC: 10334 AN: 47690

GnomAD4 genome AF: 0.207 AC: 31576 AN: 152212 Hom.: 3775 Cov.: 33 AF XY: 0.211 AC XY: 15723 AN XY: 74434

African (AFR) AF: 0.121 AC: 5014 AN: 41556

American (AMR) AF: 0.353 AC: 5404 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.231 AC: 802 AN: 3470

East Asian (EAS) AF: 0.0945 AC: 489 AN: 5176

South Asian (SAS) AF: 0.296 AC: 1428 AN: 4822

European-Finnish (FIN) AF: 0.212 AC: 2243 AN: 10604

Middle Eastern (MID) AF: 0.194 AC: 57 AN: 294

European-Non Finnish (NFE) AF: 0.226 AC: 15392 AN: 67972

Other (OTH) AF: 0.215 AC: 455 AN: 2116

Alfa AF: 0.229 Hom.: 3304

Bravo AF: 0.212

Asia WGS AF: 0.182 AC: 636 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.36
DANN	Benign	0.84
PhyloP100		-3.2
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: rs4876902; hg19: chr9-140710603; COSMIC: COSV71777913; COSMIC: COSV71777913;