rs886041001

Variant names:

• chr19-42249934-T-C
• rs886041001
• NM_006494.4:c.266A>G

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_Very_Strong

The NM_001440421.1(ERF):​c.-542A>G variant causes a 5 prime UTR premature start codon gain 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_001440421.1 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 7.95
• Publications: 10 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
• craniosynostosis 4

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, ClinGen, Ambry Genetics, G2P
• 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 14 ACMG points.

• 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 VariationId is 267443.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001440421.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ERF	NM_006494.4	MANE Select	c.266A>G	p.Tyr89Cys	missense	Exon 3 of 4	NP_006485.2	P50548-1
	ERF	NM_001440421.1		c.-542A>G		5_prime_UTR_premature_start_codon_gain	Exon 2 of 3	NP_001427350.1
	ERF	NM_001301035.2		c.41A>G	p.Tyr14Cys	missense	Exon 3 of 4	NP_001287964.1	P50548-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ERF	ENST00000222329.9	TSL:1 MANE Select	c.266A>G	p.Tyr89Cys	missense	Exon 3 of 4	ENSP00000222329.3	P50548-1
	ENSG00000268643	ENST00000594664.1	TSL:3	c.22+5044A>G		intron	N/A	ENSP00000470087.1	M0QYV0
	ERF	ENST00000595448.1	TSL:1	n.239A>G		non_coding_transcript_exon	Exon 1 of 2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
5	-	-	Chitayat syndrome (5)
2	-	-	not provided (2)
1	-	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

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
M_CAP	Uncertain	0.17	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Uncertain	0.051	D
MutationAssessor	Uncertain	2.9	M
PhyloP100		7.9
PrimateAI	Pathogenic	0.92	D
PROVEAN	Pathogenic	-9.0	D
REVEL	Pathogenic	0.76
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	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
Mutation Taster		=8/92	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: rs886041001; hg19: chr19-42754086;