rs587777007

Positions:

• chr19-42249219-CCT-C

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The NM_006494.4(ERF):​c.891_892delAG​(p.Gly299fs) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,262 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ERF NM_006494.4 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9
• Conservation: PhyloP100: 3.18

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]

ENSG00000268643 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.459 CDS is truncated, and there are 1 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 19-42249219-CCT-C is Pathogenic according to our data. Variant chr19-42249219-CCT-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 55924.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ERF	NM_006494.4	c.891_892delAG	p.Gly299fs	frameshift_variant	4/4	ENST00000222329.9	NP_006485.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ERF	ENST00000222329.9	c.891_892delAG	p.Gly299fs	frameshift_variant	4/4	1	NM_006494.4	ENSP00000222329.3
ENSG00000268643	ENST00000594664.1	c.22+5757_22+5758delAG		intron_variant		3		ENSP00000470087.1
ERF	ENST00000440177.6	c.666_667delAG	p.Gly224fs	frameshift_variant	4/4	2		ENSP00000388173.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461262 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 726936

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Craniosynostosis 4 Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	Jul 15, 2020	This ERF variant is absent in a large population dataset. It has been identified in three unrelated families with complex craniosynostosis and has an entry in ClinVar. This frameshift variant is predicted to lead to a premature stop codon in the last exon of the gene, likely escaping nonsense-mediated decay and resulting in a truncated protein product. We consider it to be likely pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Undiagnosed Diseases Network, NIH	Aug 07, 2024	Information summarized from clinical sequencing report: The c.891_892del (p.G299Rfs*9) variant in the ERF gene has been previously reported in multiple unrelated families with craniosynostosis (PMID: 23354439, 30758909, 36360262). It has been observed in gnomAD (v4) at a low frequency. This frameshift variant is located in exon 4 of 4. It is predicted to escape nonsense-mediated decay (NMD) but impact a significant portion of the protein length (250aa, 46% of the protein) or a critical region of the protein, potentially disrupting normal protein function. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 01, 2013	- -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 01, 2018

- -

TWIST1-related craniosynostosis Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Apr 29, 2022

This sequence change creates a premature translational stop signal (p.Gly299Argfs*9) in the ERF gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 250 amino acid(s) of the ERF protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with clinical features of ERF-related craniosynostosis (PMID: 28808027, 30758909). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 55924). This variant disrupts a region of the ERF protein in which other variant(s) (p.Pro358Thrfs*20) have been determined to be pathogenic (Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

See cases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genetics Laboratory, UDIAT-Centre Diagnòstic, Hospital Universitari Parc Tauli

Apr 26, 2021

PVS1_strong;PP5_strong;PM2_supporting -

Chitayat syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Mar 26, 2024

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Sep 07, 2022

Frameshift variant predicted to result in protein truncation, as the last 250 amino acids are replaced with 8 different amino acids, and other loss-of-function variants have been reported downstream in HGMD; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 23354439, 30758909) -

Craniosynostosis 4;C4310679:Chitayat syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Juno Genomics, Hangzhou Juno Genomics, Inc

-

PM2_Supporting+PVS1_Strong+PS4_Moderate+PM6+PP1+PP4 -

Computational scores

Source: dbNSFP v4.3

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: rs587777007; hg19: chr19-42753371;