19-42254999-T-C

Variant names:

• chr19-42254999-T-C
• rs864321681
• NM_006494.4:c.1A>G

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_006494.4(ERF):​c.1A>G​(p.Met1?) variant causes a start lost change involving the alteration of a non-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)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ERF NM_006494.4 start_lost
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 0.794
• Publications: 0 publications found

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]

ERF Gene-Disease associations (from GenCC):

• Chitayat syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• craniosynostosis 4

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics, PanelApp Australia, ClinGen, Genomics England PanelApp
• Crouzon syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• isolated scaphocephaly

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000268643 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 16 pathogenic variants. Next in-frame start position is after 76 codons. Genomic position: 42250362. Lost 0.137 part of the original CDS.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 19-42254999-T-C is Pathogenic according to our data. Variant chr19-42254999-T-C is described in ClinVar as Pathogenic. ClinVar VariationId is 218957.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ERF	NM_006494.4	c.1A>G	p.Met1?	start_lost	Exon 1 of 4	ENST00000222329.9	NP_006485.2
ERF	NM_001440421.1	c.-572A>G		5_prime_UTR_variant	Exon 1 of 3		NP_001427350.1
ERF	NM_001312656.2	c.-204+105A>G		intron_variant	Intron 1 of 3		NP_001299585.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ERF	ENST00000222329.9	c.1A>G	p.Met1?	start_lost	Exon 1 of 4	1	NM_006494.4	ENSP00000222329.3
ENSG00000268643	ENST00000594664.1	c.1A>G	p.Met1?	start_lost	Exon 1 of 5	3		ENSP00000470087.1
ERF	ENST00000715593.1	c.1A>G	p.Met1?	start_lost	Exon 1 of 3			ENSP00000520487.1
ERF	ENST00000596818.1	n.109A>G		non_coding_transcript_exon_variant	Exon 1 of 2	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 1302484 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 642738

African (AFR) AF: 0.00 AC: 0 AN: 25768

American (AMR) AF: 0.00 AC: 0 AN: 18638

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20250

East Asian (EAS) AF: 0.00 AC: 0 AN: 31520

South Asian (SAS) AF: 0.00 AC: 0 AN: 59422

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49094

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5002

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1039984

Other (OTH) AF: 0.00 AC: 0 AN: 52806

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Mar 01, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Identified in a patient with syndromic multiple suture synostosis in the published literature (PMID: 26097063); Initiation codon variant in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 26097063) -

Craniosynostosis 4 Pathogenic:1

Nov 01, 2015

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.050
CADD	Benign	23
DANN	Uncertain	0.98
DEOGEN2	Benign	0.17	.;T
Eigen	Benign	-0.19
Eigen_PC	Benign	-0.084
FATHMM_MKL	Benign	0.36	N
LIST_S2	Uncertain	0.90	D;D
M_CAP	Pathogenic	0.98	D
MetaRNN	Pathogenic	0.90	D;D
MetaSVM	Benign	-1.0	T
PhyloP100		0.79
PROVEAN	Benign	-0.61	.;N
REVEL	Benign	0.21
Sift	Uncertain	0.0030	.;D
Sift4G	Uncertain	0.023	D;T
Polyphen		0.055	.;B
Vest4		0.91
MutPred		1.0		Gain of methylation at K2 (P = 0.0182);Gain of methylation at K2 (P = 0.0182);
MVP		0.19
ClinPred		0.38	T
GERP RS		2.9
PromoterAI		-0.024	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.76
gMVP		0.51
Mutation Taster		=5/195	disease causing (ClinVar)

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: rs864321681; hg19: chr19-42759151;