chr9-137716856-C-G

Variant names:

• chr9-137716856-C-G
• rs144603232
• NM_024757.5:c.316C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_024757.5(EHMT1):​c.316C>G​(p.Gln106Glu) variant causes a missense change. The variant allele was found at a frequency of 0.00087 in 1,613,286 control chromosomes in the GnomAD database, including 20 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0046 (10 hom., cov: 32)
  • Exomes 𝑓: 0.00048 (10 hom.)
• Consequence: EHMT1 NM_024757.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 5.31
• Publications: 4 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 (MetaRNN=0.004447341).
• BP6: Variant 9-137716856-C-G is Benign according to our data. Variant chr9-137716856-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 128981.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00464 (707/152264) while in subpopulation AFR AF = 0.016 (663/41522). AF 95% confidence interval is 0.015. There are 10 homozygotes in GnomAd4. There are 339 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 707 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.316C>G	p.Gln106Glu	missense	Exon 3 of 27	NP_079033.4
	EHMT1	NM_001354263.2		c.316C>G	p.Gln106Glu	missense	Exon 3 of 27	NP_001341192.1
	EHMT1	NM_001354259.2		c.223C>G	p.Gln75Glu	missense	Exon 2 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.316C>G	p.Gln106Glu	missense	Exon 3 of 27	ENSP00000417980.1	Q9H9B1-1
	EHMT1	ENST00000462484.5	TSL:1	c.316C>G	p.Gln106Glu	missense	Exon 3 of 16	ENSP00000417328.1	Q9H9B1-4
	EHMT1	ENST00000896765.1		c.316C>G	p.Gln106Glu	missense	Exon 3 of 28	ENSP00000566824.1

Frequencies

GnomAD3 genomes AF: 0.00461 AC: 701 AN: 152146 Hom.: 10 Cov.: 32

Gnomad AFR AF: 0.0159

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00242

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.00114 AC: 285 AN: 250960 AF XY: 0.000921

Gnomad AFR exome AF: 0.0155

Gnomad AMR exome AF: 0.000781

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000882

Gnomad OTH exome AF: 0.000654

GnomAD4 exome AF: 0.000476 AC: 696 AN: 1461022 Hom.: 10 Cov.: 31 AF XY: 0.000405 AC XY: 294 AN XY: 726768

African (AFR) AF: 0.0163 AC: 547 AN: 33478

American (AMR) AF: 0.000828 AC: 37 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86258

European-Finnish (FIN) AF: 0.0000379 AC: 2 AN: 52720

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5764

European-Non Finnish (NFE) AF: 0.0000423 AC: 47 AN: 1111892

Other (OTH) AF: 0.000994 AC: 60 AN: 60378

GnomAD4 genome AF: 0.00464 AC: 707 AN: 152264 Hom.: 10 Cov.: 32 AF XY: 0.00455 AC XY: 339 AN XY: 74454

African (AFR) AF: 0.0160 AC: 663 AN: 41522

American (AMR) AF: 0.00242 AC: 37 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.0000941 AC: 1 AN: 10622

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

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68004

Other (OTH) AF: 0.00189 AC: 4 AN: 2112

Alfa AF: 0.00147 Hom.: 0

Bravo AF: 0.00521

ESP6500AA AF: 0.0127 AC: 56

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00130 AC: 158

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	EHMT1-related disorder (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	Kleefstra syndrome 1 (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.089	T
Eigen	Benign	0.053
Eigen_PC	Benign	0.026
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.91	D
MetaRNN	Benign	0.0044	T
MetaSVM	Benign	-0.51	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		5.3
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-0.53	N
REVEL	Benign	0.081
Sift	Benign	0.14	T
Sift4G	Benign	0.53	T
Polyphen		0.49	P
Vest4		0.45
MVP		0.59
MPC		0.077
ClinPred		0.020	T
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.14
gMVP		0.12
Mutation Taster		=99/1	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: rs144603232; hg19: chr9-140611308;