rs139206060

Variant names:

• chr9-137776773-G-A
• rs139206060
• NM_024757.5:c.1947G>A

Your query was ambiguous. Multiple possible variants found:

• chr9-137776773-G-A
• chr9-137776773-G-T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_024757.5(EHMT1):​c.1947G>A​(p.Ser649Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000812 in 1,613,998 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00017 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000072 (0 hom.)
• Consequence: EHMT1 NM_024757.5 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: 0.158
• 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: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)

ENSG00000293104 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant 9-137776773-G-A is Benign according to our data. Variant chr9-137776773-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 286384.
• BP7: Synonymous conserved (PhyloP=0.158 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000171 (26/152194) while in subpopulation AFR AF = 0.000578 (24/41514). AF 95% confidence interval is 0.000398. There are 0 homozygotes in GnomAd4. There are 13 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 26 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.1947G>A	p.Ser649Ser	synonymous	Exon 12 of 27	NP_079033.4
	EHMT1	NM_001354263.2		c.1926G>A	p.Ser642Ser	synonymous	Exon 12 of 27	NP_001341192.1
	EHMT1	NM_001354259.2		c.1854G>A	p.Ser618Ser	synonymous	Exon 11 of 16	NP_001341188.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EHMT1	ENST00000460843.6	TSL:5 MANE Select	c.1947G>A	p.Ser649Ser	synonymous	Exon 12 of 27	ENSP00000417980.1
	EHMT1	ENST00000462484.5	TSL:1	c.1947G>A	p.Ser649Ser	synonymous	Exon 12 of 16	ENSP00000417328.1
	EHMT1	ENST00000637161.1	TSL:5	c.1854G>A	p.Ser618Ser	synonymous	Exon 12 of 27	ENSP00000490328.1

Frequencies

GnomAD3 genomes AF: 0.000171 AC: 26 AN: 152076 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000580

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000215 AC: 54 AN: 251392 AF XY: 0.000221

Gnomad AFR exome AF: 0.000615

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.0000718 AC: 105 AN: 1461804 Hom.: 0 Cov.: 31 AF XY: 0.0000811 AC XY: 59 AN XY: 727204

African (AFR) AF: 0.000508 AC: 17 AN: 33480

American (AMR) AF: 0.0000447 AC: 2 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39700

South Asian (SAS) AF: 0.000812 AC: 70 AN: 86236

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53356

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1112010

Other (OTH) AF: 0.000166 AC: 10 AN: 60396

GnomAD4 genome AF: 0.000171 AC: 26 AN: 152194 Hom.: 0 Cov.: 32 AF XY: 0.000175 AC XY: 13 AN XY: 74402

African (AFR) AF: 0.000578 AC: 24 AN: 41514

American (AMR) AF: 0.00 AC: 0 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5140

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68020

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.000161 Hom.: 0

Bravo AF: 0.000170

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	not provided (2)
-	-	1	EHMT1-related disorder (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	Kleefstra syndrome 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	12
DANN	Benign	0.47
PhyloP100		0.16
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs139206060; hg19: chr9-140671225; COSMIC: COSV58383070; COSMIC: COSV58383070;