rs371136319

Variant names:

• chr9-137834830-C-T
• rs371136319
• NM_024757.5:c.3774C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_024757.5(EHMT1):​c.3774C>T​(p.Cys1258Cys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000231 in 1,612,674 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00014 (0 hom., cov: 34)
  • Exomes 𝑓: 0.00024 (1 hom.)
• Consequence: EHMT1 NM_024757.5 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.13
• 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: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.27).
• BP6: Variant 9-137834830-C-T is Benign according to our data. Variant chr9-137834830-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 366033.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.13 with no splicing effect.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000144 (22/152296) while in subpopulation EAS AF = 0.00213 (11/5168). AF 95% confidence interval is 0.00119. There are 0 homozygotes in GnomAd4. There are 11 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.
• BS2: High AC in GnomAd4 at 22 AD gene.

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.3774C>T	p.Cys1258Cys	synonymous	Exon 27 of 27	NP_079033.4
	EHMT1	NM_001354263.2		c.3753C>T	p.Cys1251Cys	synonymous	Exon 27 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.3774C>T	p.Cys1258Cys	synonymous	Exon 27 of 27	ENSP00000417980.1	Q9H9B1-1
	EHMT1	ENST00000475564.5	TSL:1	n.1498C>T		non_coding_transcript_exon	Exon 4 of 4
	EHMT1	ENST00000494249.5	TSL:1	n.1127C>T		non_coding_transcript_exon	Exon 5 of 5

Frequencies

GnomAD3 genomes AF: 0.000145 AC: 22 AN: 152180 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00212

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000210 AC: 52 AN: 247806 AF XY: 0.000223

Gnomad AFR exome AF: 0.0000625

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000544

Gnomad FIN exome AF: 0.0000925

Gnomad NFE exome AF: 0.000326

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.000240 AC: 350 AN: 1460378 Hom.: 1 Cov.: 31 AF XY: 0.000244 AC XY: 177 AN XY: 726532

African (AFR) AF: 0.00 AC: 0 AN: 33450

American (AMR) AF: 0.00 AC: 0 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26108

East Asian (EAS) AF: 0.00300 AC: 119 AN: 39680

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86242

European-Finnish (FIN) AF: 0.000247 AC: 13 AN: 52584

Middle Eastern (MID) AF: 0.000534 AC: 3 AN: 5620

European-Non Finnish (NFE) AF: 0.000175 AC: 194 AN: 1111652

Other (OTH) AF: 0.000331 AC: 20 AN: 60344

GnomAD4 genome AF: 0.000144 AC: 22 AN: 152296 Hom.: 0 Cov.: 34 AF XY: 0.000148 AC XY: 11 AN XY: 74478

African (AFR) AF: 0.0000481 AC: 2 AN: 41568

American (AMR) AF: 0.00 AC: 0 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00213 AC: 11 AN: 5168

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.0000942 AC: 1 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 68010

Other (OTH) AF: 0.00 AC: 0 AN: 2110

Alfa AF: 0.000122 Hom.: 0

Bravo AF: 0.000106

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Kleefstra syndrome 1 (2)
-	-	1	EHMT1-related disorder (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.27
CADD	Benign	6.2
DANN	Benign	0.88
PhyloP100		-1.1
Mutation Taster		=79/21	polymorphism

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: rs371136319; hg19: chr9-140729282;