rs34704821

chr9-137717066-C-Achr9-137717066-C-Gchr9-137717066-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Moderate BP6_Moderate

The NM_024757.5(EHMT1):c.526C>A(p.Pro176Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000687 in 1,455,402 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 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. P176S) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: EHMT1 NM_024757.5 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.52

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]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1436497).
• BP6: Variant 9-137717066-C-A is Benign according to our data. Variant chr9-137717066-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 1550751.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EHMT1	NM_024757.5	c.526C>A	p.Pro176Thr	missense_variant	3/27	ENST00000460843.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EHMT1	ENST00000460843.6	c.526C>A	p.Pro176Thr	missense_variant	3/27	5	NM_024757.5

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.87e-7 AC: 1 AN: 1455402 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 723082

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.02e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Kleefstra syndrome 1 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Nov 29, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.062
BayesDel_addAF	Benign	-0.027	T
BayesDel_noAF	Benign	-0.28
Cadd	Benign	14
Dann	Uncertain	0.99
DEOGEN2	Benign	0.16	T;.;T;T;.;.
Eigen	Benign	-0.58
Eigen_PC	Benign	-0.66
FATHMM_MKL	Benign	0.26	N
LIST_S2	Uncertain	0.87	D;D;D;D;D;D
M_CAP	Uncertain	0.096	D
MetaRNN	Benign	0.14	T;T;T;T;T;T
MetaSVM	Benign	-0.76	T
MutationAssessor	Uncertain	2.0	M;M;.;.;.;.
MutationTaster	Benign	0.98	N;N;N
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-1.6	N;N;.;.;.;.
REVEL	Benign	0.13
Sift	Uncertain	0.0010	D;D;.;.;.;.
Sift4G	Uncertain	0.026	D;D;.;.;D;.
Polyphen		0.23	B;P;.;.;.;.
Vest4		0.45
MutPred		0.12		Gain of phosphorylation at P176 (P = 0.0104);Gain of phosphorylation at P176 (P = 0.0104);Gain of phosphorylation at P176 (P = 0.0104);.;.;.;
MVP		0.35
MPC		0.069
ClinPred		0.37	T
GERP RS		3.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.068
gMVP		0.067

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr9-140611518;