rs767131852

Variant names:

• chr19-42248653-G-A
• rs767131852
• NM_006494.4:c.1459C>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_006494.4(ERF):​c.1459C>T​(p.Arg487Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000897 in 1,448,530 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. R487R) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000090 (0 hom.)
• Consequence: ERF NM_006494.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.74
• Publications: 2 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, ClinGen, Ambry Genetics, PanelApp Australia, Labcorp Genetics (formerly Invitae), 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: Likely_benign. The variant received -4 ACMG points.

• BS2: High AC in GnomAdExome4 at 13 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006494.4. 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.1459C>T	p.Arg487Cys	missense	Exon 4 of 4	NP_006485.2	P50548-1
	ERF	NM_001301035.2		c.1234C>T	p.Arg412Cys	missense	Exon 4 of 4	NP_001287964.1	P50548-2
	ERF	NM_001308402.2		c.1234C>T	p.Arg412Cys	missense	Exon 4 of 4	NP_001295331.1	P50548-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ERF	ENST00000222329.9	TSL:1 MANE Select	c.1459C>T	p.Arg487Cys	missense	Exon 4 of 4	ENSP00000222329.3	P50548-1
	ENSG00000268643	ENST00000594664.1	TSL:3	c.22+6325C>T		intron	N/A	ENSP00000470087.1	M0QYV0
	ERF	ENST00000440177.6	TSL:2	c.1234C>T	p.Arg412Cys	missense	Exon 4 of 4	ENSP00000388173.2	P50548-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000411 AC: 1 AN: 243410 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000108

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000897 AC: 13 AN: 1448530 Hom.: 0 Cov.: 33 AF XY: 0.00000696 AC XY: 5 AN XY: 718482

African (AFR) AF: 0.00 AC: 0 AN: 33176

American (AMR) AF: 0.00 AC: 0 AN: 43900

Ashkenazi Jewish (ASJ) AF: 0.0000393 AC: 1 AN: 25420

East Asian (EAS) AF: 0.00 AC: 0 AN: 39422

South Asian (SAS) AF: 0.00 AC: 0 AN: 85180

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52782

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5720

European-Non Finnish (NFE) AF: 0.00000997 AC: 11 AN: 1103212

Other (OTH) AF: 0.0000167 AC: 1 AN: 59718

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.060
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.70	D
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Uncertain	0.15	D
MetaRNN	Uncertain	0.42	T
MetaSVM	Benign	-0.71	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		8.7
PrimateAI	Pathogenic	0.95	D
PROVEAN	Uncertain	-3.4	D
REVEL	Uncertain	0.32
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.49
MutPred		0.52		Gain of catalytic residue at W488 (P = 5e-04)
MVP		0.57
MPC		1.8
ClinPred		0.97	D
GERP RS		4.0
Varity_R		0.30
gMVP		0.70
Mutation Taster		=19/81	disease causing

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: rs767131852; hg19: chr19-42752805; COSMIC: COSV55894920; COSMIC: COSV55894920;