9-137717066-C-T

Variant names:

• chr9-137717066-C-T
• rs34704821
• NM_024757.5:c.526C>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.526C>T​(p.Pro176Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00142 in 1,607,688 control chromosomes in the GnomAD database, including 38 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P176A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0078 (23 hom., cov: 31)
  • Exomes 𝑓: 0.00076 (15 hom.)
• Consequence: EHMT1 NM_024757.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 1.52
• Publications: 8 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, Labcorp Genetics (formerly Invitae), G2P

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.0029055178).
• BP6: Variant 9-137717066-C-T is Benign according to our data. Variant chr9-137717066-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 128982.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00779 (1186/152288) while in subpopulation AFR AF = 0.0273 (1133/41566). AF 95% confidence interval is 0.0259. There are 23 homozygotes in GnomAd4. There are 568 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1186 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EHMT1	NM_024757.5	MANE Select	c.526C>T	p.Pro176Ser	missense	Exon 3 of 27	NP_079033.4
	EHMT1	NM_001354263.2		c.526C>T	p.Pro176Ser	missense	Exon 3 of 27	NP_001341192.1
	EHMT1	NM_001354259.2		c.433C>T	p.Pro145Ser	missense	Exon 2 of 16	NP_001341188.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EHMT1	ENST00000460843.6	TSL:5 MANE Select	c.526C>T	p.Pro176Ser	missense	Exon 3 of 27	ENSP00000417980.1	Q9H9B1-1
	EHMT1	ENST00000462484.5	TSL:1	c.526C>T	p.Pro176Ser	missense	Exon 3 of 16	ENSP00000417328.1	Q9H9B1-4
	EHMT1	ENST00000896765.1		c.526C>T	p.Pro176Ser	missense	Exon 3 of 28	ENSP00000566824.1

Frequencies

GnomAD3 genomes AF: 0.00780 AC: 1187 AN: 152170 Hom.: 23 Cov.: 31

Gnomad AFR AF: 0.0274

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00210

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00479

GnomAD2 exomes AF: 0.00199 AC: 487 AN: 245242 AF XY: 0.00156

Gnomad AFR exome AF: 0.0281

Gnomad AMR exome AF: 0.00117

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000820

Gnomad OTH exome AF: 0.00168

GnomAD4 exome AF: 0.000756 AC: 1101 AN: 1455400 Hom.: 15 Cov.: 32 AF XY: 0.000672 AC XY: 486 AN XY: 723082

African (AFR) AF: 0.0260 AC: 865 AN: 33274

American (AMR) AF: 0.00124 AC: 55 AN: 44378

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26012

East Asian (EAS) AF: 0.00 AC: 0 AN: 39578

South Asian (SAS) AF: 0.0000580 AC: 5 AN: 86134

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51948

Middle Eastern (MID) AF: 0.000870 AC: 5 AN: 5744

European-Non Finnish (NFE) AF: 0.0000478 AC: 53 AN: 1108256

Other (OTH) AF: 0.00196 AC: 118 AN: 60076

GnomAD4 genome AF: 0.00779 AC: 1186 AN: 152288 Hom.: 23 Cov.: 31 AF XY: 0.00763 AC XY: 568 AN XY: 74464

African (AFR) AF: 0.0273 AC: 1133 AN: 41566

American (AMR) AF: 0.00209 AC: 32 AN: 15294

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 68020

Other (OTH) AF: 0.00474 AC: 10 AN: 2110

Alfa AF: 0.00439 Hom.: 9

Bravo AF: 0.00881

ESP6500AA AF: 0.0260 AC: 114

ESP6500EA AF: 0.000234 AC: 2

ExAC AF: 0.00238 AC: 288

EpiCase AF: 0.000273

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	Kleefstra syndrome 1 (2)
-	-	2	not specified (2)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	14
DANN	Benign	0.82
DEOGEN2	Benign	0.12	T
Eigen	Benign	-0.85
Eigen_PC	Benign	-0.83
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.77	T
MetaRNN	Benign	0.0029	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.7	L
PhyloP100		1.5
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.044
Sift	Benign	0.054	T
Sift4G	Benign	0.21	T
Polyphen		0.0080	B
Vest4		0.23
MVP		0.27
MPC		0.047
ClinPred		0.0043	T
GERP RS		3.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.032
gMVP		0.069
Mutation Taster		=98/2	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: rs34704821; hg19: chr9-140611518;