9-137813540-G-T

Variant names:

• chr9-137813540-G-T
• rs113676865
• NM_024757.5:c.3180+10G>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_024757.5(EHMT1):​c.3180+10G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00324 in 1,613,442 control chromosomes in the GnomAD database, including 50 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0027 (3 hom., cov: 33)
  • Exomes 𝑓: 0.0033 (47 hom.)
• Consequence: EHMT1 NM_024757.5 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.639
• Publications: 1 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: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 9-137813540-G-T is Benign according to our data. Variant chr9-137813540-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 96153.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00272 (414/152238) while in subpopulation SAS AF = 0.0199 (96/4814). AF 95% confidence interval is 0.0167. There are 3 homozygotes in GnomAd4. There are 233 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 414 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EHMT1	NM_024757.5	MANE Select	c.3180+10G>T		intron	N/A	NP_079033.4
	EHMT1	NM_001354263.2		c.3159+10G>T		intron	N/A	NP_001341192.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EHMT1	ENST00000460843.6	TSL:5 MANE Select	c.3180+10G>T		intron	N/A	ENSP00000417980.1
	EHMT1	ENST00000637161.1	TSL:5	c.3087+10G>T		intron	N/A	ENSP00000490328.1
	EHMT1	ENST00000462942.3	TSL:2	n.2037+10G>T		intron	N/A	ENSP00000436107.1

Frequencies

GnomAD3 genomes AF: 0.00273 AC: 415 AN: 152120 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.0187

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0199

Gnomad FIN AF: 0.00698

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00232

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00484 AC: 1206 AN: 249278 AF XY: 0.00570

Gnomad AFR exome AF: 0.000124

Gnomad AMR exome AF: 0.000551

Gnomad ASJ exome AF: 0.0202

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00621

Gnomad NFE exome AF: 0.00255

Gnomad OTH exome AF: 0.00311

GnomAD4 exome AF: 0.00329 AC: 4813 AN: 1461204 Hom.: 47 Cov.: 33 AF XY: 0.00378 AC XY: 2749 AN XY: 726850

African (AFR) AF: 0.000179 AC: 6 AN: 33480

American (AMR) AF: 0.000559 AC: 25 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.0190 AC: 497 AN: 26130

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39696

South Asian (SAS) AF: 0.0199 AC: 1711 AN: 86186

European-Finnish (FIN) AF: 0.00594 AC: 314 AN: 52906

Middle Eastern (MID) AF: 0.00364 AC: 21 AN: 5768

European-Non Finnish (NFE) AF: 0.00182 AC: 2020 AN: 1111952

Other (OTH) AF: 0.00361 AC: 218 AN: 60388

GnomAD4 genome AF: 0.00272 AC: 414 AN: 152238 Hom.: 3 Cov.: 33 AF XY: 0.00313 AC XY: 233 AN XY: 74428

African (AFR) AF: 0.000241 AC: 10 AN: 41540

American (AMR) AF: 0.000327 AC: 5 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0187 AC: 65 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.0199 AC: 96 AN: 4814

European-Finnish (FIN) AF: 0.00698 AC: 74 AN: 10596

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00232 AC: 158 AN: 68018

Other (OTH) AF: 0.00236 AC: 5 AN: 2116

Alfa AF: 0.00406 Hom.: 0

Bravo AF: 0.00148

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Jul 26, 2018

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not specified Benign:1

Oct 21, 2013

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Kleefstra syndrome 1 Benign:1

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.20
DANN	Benign	0.23
PhyloP100		0.64
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs113676865; hg19: chr9-140707992;