rs1354730657

chr9-137743370-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 6P and 2B. PVS1_Moderate PP3_Strong BP6_Moderate

The NM_024757.5(EHMT1):c.824-1G>T variant causes a splice acceptor 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 Likely benign (★).

• 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
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.39

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PVS1: Splicing variant, NOT destroyed by nmd, known LOF gene, truncates exone, which is 0.0402874 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.
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• BP6: Variant 9-137743370-G-T is Benign according to our data. Variant chr9-137743370-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 445623.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-137743370-G-T is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EHMT1	NM_024757.5	c.824-1G>T		splice_acceptor_variant		ENST00000460843.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EHMT1	ENST00000460843.6	c.824-1G>T		splice_acceptor_variant		5	NM_024757.5

Frequencies

GnomAD3 genomes AF: 0.00 AC: 13 AN: 135320 Hom.: 0 Cov.: 31 FAILED QC

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

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

Gnomad4 AFR exome AF: 0.000164

Gnomad4 AMR exome AF: 0.00103

Gnomad4 ASJ exome AF: 0.0000804

Gnomad4 EAS exome AF: 0.0000267

Gnomad4 SAS exome AF: 0.0000508

Gnomad4 FIN exome AF: 0.000148

Gnomad4 NFE exome AF: 0.0000229

Gnomad4 OTH exome AF: 0.000121

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

Gnomad4 AFR AF: 0.0000550

Gnomad4 AMR AF: 0.0000743

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000236

Gnomad4 FIN AF: 0.000646

Gnomad4 NFE AF: 0.0000640

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

May 24, 2017

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Computational scores

Source: dbNSFP v4.3

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
MutationTaster	Benign	1.0	D;D;D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

Publications

LitVar

Other links and lift over

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