NM_024757.5:c.824-1G>T

Variant names:

• chr9-137743370-G-T
• rs1354730657
• NM_024757.5:c.824-1G>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PVS1_Moderate BP6

The NM_024757.5(EHMT1):​c.824-1G>T variant causes a splice acceptor, intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000096 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000063 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: EHMT1 NM_024757.5 splice_acceptor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 2.39
• Publications: 0 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: Uncertain_significance. The variant received 1 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.040544007 fraction of the gene. Cryptic splice site detected, with MaxEntScore 8, offset of 21, new splice context is: ttgcttgccttttgttttAGcag. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• BP6: Variant 9-137743370-G-T is Benign according to our data. Variant chr9-137743370-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 445623.

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.824-1G>T		splice_acceptor intron	N/A	NP_079033.4
	EHMT1	NM_001354263.2		c.824-22G>T		intron	N/A	NP_001341192.1
	EHMT1	NM_001354259.2		c.731-1G>T		splice_acceptor intron	N/A	NP_001341188.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EHMT1	ENST00000460843.6	TSL:5 MANE Select	c.824-1G>T		splice_acceptor intron	N/A	ENSP00000417980.1	Q9H9B1-1
	EHMT1	ENST00000462484.5	TSL:1	c.824-1G>T		splice_acceptor intron	N/A	ENSP00000417328.1	Q9H9B1-4
	EHMT1	ENST00000896765.1		c.917-22G>T		intron	N/A	ENSP00000566824.1

Frequencies

GnomAD3 genomes AF: 0.0000961 AC: 13 AN: 135320 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000550

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000743

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000236

Gnomad FIN AF: 0.000646

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000640

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000110 AC: 20 AN: 181252 AF XY: 0.000120

Gnomad AFR exome AF: 0.0000868

Gnomad AMR exome AF: 0.0000780

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000117

Gnomad OTH exome AF: 0.000222

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000635 AC: 89 AN: 1401980 Hom.: 0 Cov.: 35 AF XY: 0.0000531 AC XY: 37 AN XY: 696308

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

African (AFR) AF: 0.000164 AC: 5 AN: 30420

American (AMR) AF: 0.00103 AC: 38 AN: 37038

Ashkenazi Jewish (ASJ) AF: 0.0000804 AC: 2 AN: 24886

East Asian (EAS) AF: 0.0000267 AC: 1 AN: 37398

South Asian (SAS) AF: 0.0000508 AC: 4 AN: 78722

European-Finnish (FIN) AF: 0.000148 AC: 6 AN: 40474

Middle Eastern (MID) AF: 0.000191 AC: 1 AN: 5228

European-Non Finnish (NFE) AF: 0.0000229 AC: 25 AN: 1089832

Other (OTH) AF: 0.000121 AC: 7 AN: 57982

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000961 AC: 13 AN: 135320 Hom.: 0 Cov.: 31 AF XY: 0.000108 AC XY: 7 AN XY: 65096

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

African (AFR) AF: 0.0000550 AC: 2 AN: 36342

American (AMR) AF: 0.0000743 AC: 1 AN: 13464

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3242

East Asian (EAS) AF: 0.00 AC: 0 AN: 4828

South Asian (SAS) AF: 0.000236 AC: 1 AN: 4244

European-Finnish (FIN) AF: 0.000646 AC: 5 AN: 7734

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 298

European-Non Finnish (NFE) AF: 0.0000640 AC: 4 AN: 62526

Other (OTH) AF: 0.00 AC: 0 AN: 1830

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	-	Kleefstra syndrome (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.24
CADD	Pathogenic	32
DANN	Uncertain	0.99
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Uncertain	0.91	D
PhyloP100		2.4
GERP RS		5.4
PromoterAI		-0.0062	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=9/91	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		0.91		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.91		Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1354730657; hg19: chr9-140637822; COSMIC: COSV58376238; COSMIC: COSV58376238;