9-137619040-C-A

Variant names:

• chr9-137619040-C-A
• rs931986426
• NM_024757.5:c.12C>A

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BP6_Moderate BP7 BS2_Supporting

The NM_024757.5(EHMT1):​c.12C>A​(p.Ala4Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000727 in 963,340 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 Likely benign (★). Synonymous variant affecting the same amino acid position (i.e. A4A) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.000034 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000024 (0 hom.)
• Consequence: EHMT1 NM_024757.5 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.185
• 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: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.47).
• BP6: Variant 9-137619040-C-A is Benign according to our data. Variant chr9-137619040-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 940094.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-0.185 with no splicing effect.
• BS2: High AC in GnomAd4 at 5 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EHMT1	NM_024757.5	c.12C>A	p.Ala4Ala	synonymous_variant	Exon 1 of 27	ENST00000460843.6	NP_079033.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EHMT1	ENST00000460843.6	c.12C>A	p.Ala4Ala	synonymous_variant	Exon 1 of 27	5	NM_024757.5	ENSP00000417980.1

Frequencies

GnomAD3 genomes AF: 0.0000342 AC: 5 AN: 146056 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000982

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000197

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000245 AC: 2 AN: 817284 Hom.: 0 Cov.: 16 AF XY: 0.00000265 AC XY: 1 AN XY: 377960

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 15470

American (AMR) AF: 0.00 AC: 0 AN: 1068

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 5142

East Asian (EAS) AF: 0.00 AC: 0 AN: 3622

South Asian (SAS) AF: 0.00 AC: 0 AN: 16920

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 484

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1598

European-Non Finnish (NFE) AF: 0.00000268 AC: 2 AN: 746214

Other (OTH) AF: 0.00 AC: 0 AN: 26766

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000081), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000342 AC: 5 AN: 146056 Hom.: 0 Cov.: 31 AF XY: 0.0000704 AC XY: 5 AN XY: 71006

African (AFR) AF: 0.0000982 AC: 4 AN: 40750

American (AMR) AF: 0.00 AC: 0 AN: 14720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3390

East Asian (EAS) AF: 0.000197 AC: 1 AN: 5088

South Asian (SAS) AF: 0.00 AC: 0 AN: 4812

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8310

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 308

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 65764

Other (OTH) AF: 0.00 AC: 0 AN: 2006

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000567

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Kleefstra syndrome 1 Benign:1

May 06, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.47
CADD	Benign	12
DANN	Benign	0.86
PhyloP100		-0.18
PromoterAI		-0.090	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs931986426; hg19: chr9-140513492;