Genetic Variant EHMT1:p.Met1? (chr9-137619030-T-C) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PVS1_SupportingPM2

The NM_024757.5(EHMT1):c.2T>C(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000207 in 966,842 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: 𝑓 0.0000069 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000012 ( 0 hom. )

Consequence

EHMT1
NM_024757.5 start_lost

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.599

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 made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PVS1

Start lost variant, no pathogenic variants between lost start and next in-frame start position. 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.2T>C	p.Met1?	start_lost	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.2T>C	p.Met1?	start_lost	Exon 1 of 27	5	NM_024757.5	ENSP00000417980.1		Q9H9B1-1

Frequencies

GnomAD3 genomes

AF:

0.00000688

AC:

AN:

145246

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000247

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.00

GnomAD4 exome

AF:

0.00000122

AC:

AN:

821596

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

379920

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000133

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000688

AC:

AN:

145246

Hom.:

Cov.:

AF XY:

0.0000142

AC XY:

AN XY:

70628

show subpopulations

Gnomad4 AFR

AF:

0.0000247

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.63

BayesDel_noAF

Benign

-0.23

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Benign

0.050

T;.;T

Eigen

Benign

-0.41

Eigen_PC

Benign

-0.44

FATHMM_MKL

Benign

0.13

LIST_S2

Uncertain

0.90

D;D;D

M_CAP

Pathogenic

0.97

MetaRNN

Pathogenic

0.97

D;D;D

MetaSVM

Benign

-0.68

PROVEAN

Benign

-0.50

N;N;.

REVEL

Benign

0.19

Sift

Pathogenic

0.0

D;D;.

Sift4G

Pathogenic

0.0

D;D;.

Polyphen

0.0

B;P;.

Vest4

0.65

MutPred

0.97

Gain of glycosylation at M1 (P = 0.0023);Gain of glycosylation at M1 (P = 0.0023);Gain of glycosylation at M1 (P = 0.0023);

MVP

0.68

ClinPred

0.14

GERP RS

1.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.62

gMVP

0.12

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over