19-42248476-G-C

Variant names:

• chr19-42248476-G-C
• rs764412749
• NM_006494.4:c.1636C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_006494.4(ERF):​c.1636C>G​(p.Arg546Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R546Q) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ERF NM_006494.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0250
• Publications: 1 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.093238175).

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.1636C>G	p.Arg546Gly	missense	Exon 4 of 4	NP_006485.2	P50548-1
	ERF	NM_001301035.2		c.1411C>G	p.Arg471Gly	missense	Exon 4 of 4	NP_001287964.1	P50548-2
	ERF	NM_001308402.2		c.1411C>G	p.Arg471Gly	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.1636C>G	p.Arg546Gly	missense	Exon 4 of 4	ENSP00000222329.3	P50548-1
	ENSG00000268643	ENST00000594664.1	TSL:3	c.22+6502C>G		intron	N/A	ENSP00000470087.1	M0QYV0
	ERF	ENST00000440177.6	TSL:2	c.1411C>G	p.Arg471Gly	missense	Exon 4 of 4	ENSP00000388173.2	P50548-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	21
DANN	Benign	0.97
DEOGEN2	Benign	0.23	T
Eigen	Benign	-0.66
Eigen_PC	Benign	-0.55
FATHMM_MKL	Benign	0.47	N
LIST_S2	Benign	0.80	T
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.093	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.34	N
PhyloP100		-0.025
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-0.85	N
REVEL	Benign	0.18
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.011	D
Polyphen		0.015	B
Vest4		0.32
MutPred		0.17		Gain of relative solvent accessibility (P = 0.0275)
MVP		0.35
MPC		0.89
ClinPred		0.11	T
GERP RS		3.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.10
gMVP		0.10
Mutation Taster		=92/8	polymorphism

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: rs764412749; hg19: chr19-42752628;