NM_024757.5:c.1162G>A

Variant names:

• chr9-137744082-G-A
• rs11137198
• NM_024757.5:c.1162G>A

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.1162G>A​(p.Ala388Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0179 in 1,613,972 control chromosomes in the GnomAD database, including 341 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.013 (20 hom., cov: 33)
  • Exomes 𝑓: 0.018 (321 hom.)
• Consequence: EHMT1 NM_024757.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.0970
• Publications: 9 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0038109422).
• BP6: Variant 9-137744082-G-A is Benign according to our data. Variant chr9-137744082-G-A is described in ClinVar as Benign. ClinVar VariationId is 128975.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0128 (1955/152288) while in subpopulation NFE AF = 0.0183 (1244/68028). AF 95% confidence interval is 0.0174. There are 20 homozygotes in GnomAd4. There are 962 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1955 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EHMT1	NM_024757.5	MANE Select	c.1162G>A	p.Ala388Thr	missense	Exon 6 of 27	NP_079033.4
	EHMT1	NM_001354263.2		c.1141G>A	p.Ala381Thr	missense	Exon 6 of 27	NP_001341192.1
	EHMT1	NM_001354259.2		c.1069G>A	p.Ala357Thr	missense	Exon 5 of 16	NP_001341188.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EHMT1	ENST00000460843.6	TSL:5 MANE Select	c.1162G>A	p.Ala388Thr	missense	Exon 6 of 27	ENSP00000417980.1
	EHMT1	ENST00000462484.5	TSL:1	c.1162G>A	p.Ala388Thr	missense	Exon 6 of 16	ENSP00000417328.1
	EHMT1	ENST00000637161.1	TSL:5	c.1069G>A	p.Ala357Thr	missense	Exon 6 of 27	ENSP00000490328.1

Frequencies

GnomAD3 genomes AF: 0.0128 AC: 1955 AN: 152170 Hom.: 20 Cov.: 33

Gnomad AFR AF: 0.00323

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0123

Gnomad ASJ AF: 0.0121

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0110

Gnomad FIN AF: 0.0253

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0183

Gnomad OTH AF: 0.0115

GnomAD2 exomes AF: 0.0135 AC: 3382 AN: 249848 AF XY: 0.0139

Gnomad AFR exome AF: 0.00333

Gnomad AMR exome AF: 0.00746

Gnomad ASJ exome AF: 0.0128

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.0224

Gnomad NFE exome AF: 0.0178

Gnomad OTH exome AF: 0.0165

GnomAD4 exome AF: 0.0184 AC: 26939 AN: 1461684 Hom.: 321 Cov.: 34 AF XY: 0.0185 AC XY: 13454 AN XY: 727150

African (AFR) AF: 0.00257 AC: 86 AN: 33480

American (AMR) AF: 0.00754 AC: 337 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0126 AC: 329 AN: 26134

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39700

South Asian (SAS) AF: 0.0126 AC: 1083 AN: 86254

European-Finnish (FIN) AF: 0.0226 AC: 1205 AN: 53246

Middle Eastern (MID) AF: 0.00381 AC: 22 AN: 5768

European-Non Finnish (NFE) AF: 0.0206 AC: 22927 AN: 1111984

Other (OTH) AF: 0.0157 AC: 946 AN: 60394

GnomAD4 genome AF: 0.0128 AC: 1955 AN: 152288 Hom.: 20 Cov.: 33 AF XY: 0.0129 AC XY: 962 AN XY: 74478

African (AFR) AF: 0.00322 AC: 134 AN: 41566

American (AMR) AF: 0.0123 AC: 188 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0121 AC: 42 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.0110 AC: 53 AN: 4828

European-Finnish (FIN) AF: 0.0253 AC: 268 AN: 10602

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0183 AC: 1244 AN: 68028

Other (OTH) AF: 0.0114 AC: 24 AN: 2114

Alfa AF: 0.0154 Hom.: 74

Bravo AF: 0.0112

ESP6500AA AF: 0.00363 AC: 16

ESP6500EA AF: 0.0217 AC: 187

ExAC AF: 0.0135 AC: 1639

Asia WGS AF: 0.00231 AC: 9 AN: 3478

EpiCase AF: 0.0176

EpiControl AF: 0.0166

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	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	0.065
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	2.9
DANN	Benign	0.88
DEOGEN2	Benign	0.048	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.047	N
LIST_S2	Benign	0.72	T
MetaRNN	Benign	0.0038	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.35	N
PhyloP100		0.097
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.20	N
REVEL	Benign	0.019
Sift	Benign	0.28	T
Sift4G	Benign	0.56	T
Polyphen		0.0020	B
Vest4		0.0090
MPC		0.045
ClinPred		0.0013	T
GERP RS		-0.31
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.056
gMVP		0.062
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: rs11137198; hg19: chr9-140638534; COSMIC: COSV108171985;