Genetic Variant EHMT1:p.Met1? (chr9-137619029-A-T) – ACMG Classification: Pathogenic (10 pts)

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1PM2

The NM_024757.5(EHMT1):c.1A>T(p.Met1?) variant causes a initiator codon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000485 in 823,952 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000049 ( 0 hom. )

Consequence

EHMT1
NM_024757.5 initiator_codon

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.58

Publications

0 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 links:

ENSG00000283411 (HGNC:):

ENSG00000283411 links:

ARRDC1-AS1 (HGNC:23395): (ARRDC1 antisense RNA 1) This transcribed locus is thought to be non-coding. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jun 2014]

ARRDC1-AS1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 10 ACMG points.

PVS1

Start lost variant, next in-frame start position is after 7 pathogenic variants. Next in-frame start position is after 32 codons. Genomic position: 137716634. Lost 0.024 part of the original CDS.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EHMT1	NM_024757.5 link	c.1A>T	p.Met1?	initiator_codon_variant	Exon 1 of 27	ENST00000460843.6	NP_079033.4	Q9H9B1-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EHMT1	ENST00000460843.6 link	c.1A>T	p.Met1?	initiator_codon_variant	Exon 1 of 27	5	NM_024757.5	ENSP00000417980.1		Q9H9B1-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000485

AC:

AN:

823952

Hom.:

Cov.:

AF XY:

0.00000525

AC XY:

AN XY:

381028

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

15560

American (AMR)

AF:

0.00

AC:

AN:

1096

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

5174

East Asian (EAS)

AF:

0.00

AC:

AN:

3672

South Asian (SAS)

AF:

0.00

AC:

AN:

17020

European-Finnish (FIN)

AF:

0.00

AC:

AN:

590

Middle Eastern (MID)

AF:

0.00

AC:

AN:

1618

European-Non Finnish (NFE)

AF:

0.00000532

AC:

AN:

752186

Other (OTH)

AF:

0.00

AC:

AN:

27036

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.007931), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.400

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.0043

BayesDel_noAF

Benign

-0.24

CADD

Benign

(source)

DANN

Benign

0.77

DEOGEN2

Benign

0.050

T;.;T

Eigen

Benign

-0.62

Eigen_PC

Benign

-0.64

FATHMM_MKL

Benign

0.065

LIST_S2

Uncertain

0.90

D;D;D

M_CAP

Pathogenic

0.95

MetaRNN

Pathogenic

0.89

D;D;D

MetaSVM

Benign

-0.87

PhyloP100

1.6

PROVEAN

Benign

-0.27

N;N;.

REVEL

Benign

0.13

Sift

Pathogenic

0.0

D;D;.

Sift4G

Pathogenic

0.0

D;D;.

Polyphen

0.0

B;B;.

Vest4

0.71

MutPred

0.97

Gain of stability (P = 0.0742);Gain of stability (P = 0.0742);Gain of stability (P = 0.0742);

MVP

0.65

ClinPred

0.39

GERP RS

0.15

PromoterAI

-0.46

Neutral

(source)

Varity_R

0.70

gMVP

0.073

Mutation Taster

=27/173

disease causing

(source)

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

Publications

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9-137619029-A-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over