NM_024757.5:c.13G>A

Variant names:

• chr9-137619041-G-A
• rs1050977100
• NM_024757.5:c.13G>A

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BP6

The NM_024757.5(EHMT1):​c.13G>A​(p.Asp5Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D5Y) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: EHMT1 NM_024757.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 1.03
• 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]

ENSG00000283411 (HGNC:):

ARRDC1-AS1 (HGNC:23395): (ARRDC1 antisense RNA 1) This transcribed locus is thought to be non-coding. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jun 2014]

ACMG classification

Our verdict: Likely_benign. The variant received -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.17859966).
• BP6: Variant 9-137619041-G-A is Benign according to our data. Variant chr9-137619041-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1204537.

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.13G>A	p.Asp5Asn	missense	Exon 1 of 27	NP_079033.4
	EHMT1	NM_001354263.2		c.13G>A	p.Asp5Asn	missense	Exon 1 of 27	NP_001341192.1
	EHMT1	NM_001145527.2		c.13G>A	p.Asp5Asn	missense	Exon 1 of 16	NP_001138999.1	Q9H9B1-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EHMT1	ENST00000460843.6	TSL:5 MANE Select	c.13G>A	p.Asp5Asn	missense	Exon 1 of 27	ENSP00000417980.1	Q9H9B1-1
	EHMT1	ENST00000462484.5	TSL:1	c.13G>A	p.Asp5Asn	missense	Exon 1 of 16	ENSP00000417328.1	Q9H9B1-4
	EHMT1	ENST00000896765.1		c.13G>A	p.Asp5Asn	missense	Exon 1 of 28	ENSP00000566824.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 815156 Hom.: 0 Cov.: 15 AF XY: 0.00 AC XY: 0 AN XY: 376906

African (AFR) AF: 0.00 AC: 0 AN: 15436

American (AMR) AF: 0.00 AC: 0 AN: 1056

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 5130

East Asian (EAS) AF: 0.00 AC: 0 AN: 3606

South Asian (SAS) AF: 0.00 AC: 0 AN: 16862

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 478

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1600

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 744282

Other (OTH) AF: 0.00 AC: 0 AN: 26706

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	-	Kleefstra syndrome 1 (1)
-	-	1	not provided (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.39
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.51
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Benign	0.056	T
Eigen	Benign	-0.68
Eigen_PC	Benign	-0.66
FATHMM_MKL	Benign	0.19	N
LIST_S2	Benign	0.56	T
M_CAP	Pathogenic	0.91	D
MetaRNN	Benign	0.18	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.34	N
PhyloP100		1.0
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-0.29	N
REVEL	Benign	0.054
Sift	Uncertain	0.019	D
Sift4G	Benign	0.16	T
Polyphen		0.0020	B
Vest4		0.16
MutPred		0.14		Loss of loop (P = 0.1242)
MVP		0.44
MPC		0.045
ClinPred		0.13	T
GERP RS		0.16
PromoterAI		-0.075	Neutral
Varity_R		0.069
gMVP		0.069
Mutation Taster		=93/7	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: rs1050977100; hg19: chr9-140513493;