rs757476606

Variant names:

• chr9-137716764-A-G
• rs757476606
• NM_024757.5:c.224A>G

Your query was ambiguous. Multiple possible variants found:

• chr9-137716764-A-G
• chr9-137716764-A-T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Moderate BP6_Very_Strong BS2

The NM_024757.5(EHMT1):​c.224A>G​(p.Asp75Gly) variant causes a missense change. The variant allele was found at a frequency of 0.0000397 in 1,460,804 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 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. D75H) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000040 (0 hom.)
• Consequence: EHMT1 NM_024757.5 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 6.28
• 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.1780096).
• BP6: Variant 9-137716764-A-G is Benign according to our data. Variant chr9-137716764-A-G is described in ClinVar as Likely_benign. ClinVar VariationId is 571740.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAdExome4 at 58 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.224A>G	p.Asp75Gly	missense	Exon 3 of 27	NP_079033.4
	EHMT1	NM_001354263.2		c.224A>G	p.Asp75Gly	missense	Exon 3 of 27	NP_001341192.1
	EHMT1	NM_001354259.2		c.131A>G	p.Asp44Gly	missense	Exon 2 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.224A>G	p.Asp75Gly	missense	Exon 3 of 27	ENSP00000417980.1
	EHMT1	ENST00000462484.5	TSL:1	c.224A>G	p.Asp75Gly	missense	Exon 3 of 16	ENSP00000417328.1
	EHMT1	ENST00000637161.1	TSL:5	c.131A>G	p.Asp44Gly	missense	Exon 3 of 27	ENSP00000490328.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000160 AC: 4 AN: 250696 AF XY: 0.00000737

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000353

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000397 AC: 58 AN: 1460804 Hom.: 0 Cov.: 31 AF XY: 0.0000275 AC XY: 20 AN XY: 726674

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44692

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26108

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52666

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.0000513 AC: 57 AN: 1111774

Other (OTH) AF: 0.0000166 AC: 1 AN: 60366

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000282 Hom.: 0

Bravo AF: 0.00000756

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Inborn genetic diseases (1)
-	-	1	Kleefstra syndrome 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.11	T
Eigen	Uncertain	0.23
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.88	D
M_CAP	Uncertain	0.25	D
MetaRNN	Benign	0.18	T
MetaSVM	Uncertain	-0.025	T
MutationAssessor	Benign	0.55	N
PhyloP100		6.3
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.14
Sift	Uncertain	0.0020	D
Sift4G	Benign	0.17	T
Polyphen		0.38	B
Vest4		0.32
MutPred		0.15		Gain of sheet (P = 0.0344)
MVP		0.44
MPC		0.12
ClinPred		0.27	T
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.20
gMVP		0.18
Mutation Taster		=75/25	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: rs757476606; hg19: chr9-140611216;