dbSNP rs184814386: EHMT1:p.Asn622Ser (chr9-137776691-A-G) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_024757.5(EHMT1):c.1865A>G(p.Asn622Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000793 in 1,614,146 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N622D) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00034 ( 1 hom., cov: 32)

Exomes 𝑓: 0.000052 ( 0 hom. )

Consequence

EHMT1
NM_024757.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:4

Conservation

PhyloP100: 3.41

Publications

3 publications found

Variant links:

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)

EHMT1 links:

ENSG00000293104 (HGNC:):

ENSG00000293104 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.02147004).

BP6

Variant 9-137776691-A-G is Benign according to our data. Variant chr9-137776691-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 128977.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000341 (52/152286) while in subpopulation AMR AF = 0.00294 (45/15304). AF 95% confidence interval is 0.00226. There are 1 homozygotes in GnomAd4. There are 28 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 52 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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
EHMT1	NM_024757.5	MANE Select	c.1865A>G	p.Asn622Ser	missense	Exon 12 of 27	NP_079033.4
EHMT1	NM_001354263.2		c.1844A>G	p.Asn615Ser	missense	Exon 12 of 27	NP_001341192.1
EHMT1	NM_001354259.2		c.1772A>G	p.Asn591Ser	missense	Exon 11 of 16	NP_001341188.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
EHMT1	ENST00000460843.6	TSL:5 MANE Select	c.1865A>G	p.Asn622Ser	missense	Exon 12 of 27	ENSP00000417980.1	Q9H9B1-1
EHMT1	ENST00000462484.5	TSL:1	c.1865A>G	p.Asn622Ser	missense	Exon 12 of 16	ENSP00000417328.1	Q9H9B1-4
EHMT1	ENST00000896765.1		c.1937A>G	p.Asn646Ser	missense	Exon 13 of 28	ENSP00000566824.1

Frequencies

GnomAD3 genomes

AF:

0.000342

AC:

AN:

152168

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00294

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000957

GnomAD2 exomes

AF:

0.0000875

AC:

AN:

251490

AF XY:

0.0000736

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.000347

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000352

Gnomad OTH exome

AF:

0.000652

GnomAD4 exome

AF:

0.0000520

AC:

AN:

1461860

Hom.:

Cov.:

AF XY:

0.0000523

AC XY:

AN XY:

727228

show subpopulations

African (AFR)

AF:

0.0000896

AC:

AN:

33480

American (AMR)

AF:

0.000537

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53394

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000315

AC:

AN:

1112006

Other (OTH)

AF:

0.000215

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000341

AC:

AN:

152286

Hom.:

Cov.:

AF XY:

0.000376

AC XY:

AN XY:

74466

show subpopulations

African (AFR)

AF:

0.000120

AC:

AN:

41566

American (AMR)

AF:

0.00294

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5166

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68016

Other (OTH)

AF:

0.000947

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000128

Hom.:

Bravo

AF:

0.000820

ExAC

AF:

0.0000659

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

EHMT1-related disorder (1)

Inborn genetic diseases (1)

Kleefstra syndrome 1 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.078

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.49

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.19

Eigen

Benign

-0.078

Eigen_PC

Benign

0.026

FATHMM_MKL

Uncertain

0.91

LIST_S2

Uncertain

0.87

M_CAP

Benign

0.027

MetaRNN

Benign

0.021

MetaSVM

Benign

-0.59

MutationAssessor

Uncertain

2.4

PhyloP100

3.4

PrimateAI

Benign

0.36

PROVEAN

Uncertain

-2.5

REVEL

Benign

0.15

Sift

Uncertain

0.017

Sift4G

Benign

0.14

Polyphen

0.0050

Vest4

0.13

MVP

0.65

MPC

0.57

ClinPred

0.13

GERP RS

4.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.090

gMVP

0.26

Mutation Taster

=96/4

polymorphism

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over