rs886041001

chr19-42249934-T-C

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PP3_Strong PP5_Very_Strong

The NM_006494.4(ERF):c.266A>G(p.Tyr89Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ERF NM_006494.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 7.95

Genes affected

ERF (HGNC:3444): (ETS2 repressor factor) ETS2 is a transcription factor and protooncogene involved in development, apoptosis, and the regulation of telomerase. The protein encoded by this gene binds to the ETS2 promoter and is a strong repressor of ETS2 transcription. Several transcript variants encoding two different isoforms have been found for this gene. [provided by RefSeq, Aug 2015]

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_006494.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.986
• PP5: Variant 19-42249934-T-C is Pathogenic according to our data. Variant chr19-42249934-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 267443.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ERF	NM_006494.4	c.266A>G	p.Tyr89Cys	missense_variant	3/4	ENST00000222329.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ERF	ENST00000222329.9	c.266A>G	p.Tyr89Cys	missense_variant	3/4	1	NM_006494.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Chitayat syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Molecular Genetics Lab, CHRU Brest	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 21, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Mar 22, 2022	Same or different nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000267443). The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 30569521, 27738187). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.764>=0.6, 3CNET: 0.97>=0.75). It is not observed in the gnomAD v2.1.1 dataset. Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 06, 2022	Not observed in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 30569521, 27738187, 30728880, 30758909, 32592542, 34426522, 31785789) -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 17, 2021

The c.266A>G (p.Y89C) alteration is located in exon 3 (coding exon 3) of the ERF gene. This alteration results from a A to G substitution at nucleotide position 266, causing the tyrosine (Y) at amino acid position 89 to be replaced by a cysteine (C). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This alteration is a recurrent alteration reported in multiple unrelated individuals with Chitayat syndrome. This alteration occurred de novo in at least three separate patients and was inherited from an affected parent in two families (Balasubramanian, 2016; Caro-Contreras, 2019; Shin, 2019; Suter, 2020; Ambry internal data). This amino acid position is highly conserved in available vertebrate species. The in silico prediction for this alteration is inconclusive. Based on the available evidence, this alteration is classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
Cadd	Pathogenic	32
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.92	D;.;.;.
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	1.0	D;D;D;D
M_CAP	Uncertain	0.17	D
MetaRNN	Pathogenic	0.99	D;D;D;D
MetaSVM	Uncertain	0.051	D
MutationAssessor	Uncertain	2.9	M;.;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.92	D
PROVEAN	Pathogenic	-9.0	D;D;.;.
REVEL	Pathogenic	0.76
Sift	Pathogenic	0.0	D;D;.;.
Sift4G	Pathogenic	0.0	D;D;D;.
Polyphen		1.0	D;.;.;.
Vest4		0.90
MutPred		0.94		Gain of methylation at K91 (P = 0.0623);.;.;.;
MVP		0.74
MPC		1.8
ClinPred		1.0	D
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.98
gMVP		0.91

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

LitVar

Other links and lift over

dbSNP: rs886041001; hg19: chr19-42754086;