rs139842507

Variant names:

• chr19-42248868-G-A
• rs139842507
• NM_006494.4:c.1244C>T

Your query was ambiguous. Multiple possible variants found:

• chr19-42248868-G-A
• chr19-42248868-G-C
• chr19-42248868-G-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_006494.4(ERF):​c.1244C>T​(p.Ala415Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0174 in 1,607,218 control chromosomes in the GnomAD database, including 276 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. A415A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.012 (13 hom., cov: 32)
  • Exomes 𝑓: 0.018 (263 hom.)
• Consequence: ERF NM_006494.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.0350
• Publications: 4 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.002723068).
• BP6: Variant 19-42248868-G-A is Benign according to our data. Variant chr19-42248868-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 476625.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0117 (1781/152190) while in subpopulation NFE AF = 0.0182 (1240/67964). AF 95% confidence interval is 0.0174. There are 13 homozygotes in GnomAd4. There are 868 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1781 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ERF	NM_006494.4	MANE Select	c.1244C>T	p.Ala415Val	missense	Exon 4 of 4	NP_006485.2
	ERF	NM_001301035.2		c.1019C>T	p.Ala340Val	missense	Exon 4 of 4	NP_001287964.1
	ERF	NM_001308402.2		c.1019C>T	p.Ala340Val	missense	Exon 4 of 4	NP_001295331.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ERF	ENST00000222329.9	TSL:1 MANE Select	c.1244C>T	p.Ala415Val	missense	Exon 4 of 4	ENSP00000222329.3
	ENSG00000268643	ENST00000594664.1	TSL:3	c.22+6110C>T		intron	N/A	ENSP00000470087.1
	ERF	ENST00000440177.6	TSL:2	c.1019C>T	p.Ala340Val	missense	Exon 4 of 4	ENSP00000388173.2

Frequencies

GnomAD3 genomes AF: 0.0117 AC: 1781 AN: 152074 Hom.: 13 Cov.: 32

Gnomad AFR AF: 0.00312

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00635

Gnomad ASJ AF: 0.00634

Gnomad EAS AF: 0.00791

Gnomad SAS AF: 0.00705

Gnomad FIN AF: 0.0193

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0182

Gnomad OTH AF: 0.00574

GnomAD2 exomes AF: 0.0140 AC: 3275 AN: 233218 AF XY: 0.0142

Gnomad AFR exome AF: 0.00363

Gnomad AMR exome AF: 0.00562

Gnomad ASJ exome AF: 0.00614

Gnomad EAS exome AF: 0.00568

Gnomad FIN exome AF: 0.0211

Gnomad NFE exome AF: 0.0206

Gnomad OTH exome AF: 0.0126

GnomAD4 exome AF: 0.0180 AC: 26133 AN: 1455028 Hom.: 263 Cov.: 33 AF XY: 0.0177 AC XY: 12820 AN XY: 723626

African (AFR) AF: 0.00287 AC: 96 AN: 33416

American (AMR) AF: 0.00586 AC: 261 AN: 44564

Ashkenazi Jewish (ASJ) AF: 0.00658 AC: 171 AN: 25996

East Asian (EAS) AF: 0.0136 AC: 537 AN: 39612

South Asian (SAS) AF: 0.00982 AC: 845 AN: 86010

European-Finnish (FIN) AF: 0.0191 AC: 938 AN: 49132

Middle Eastern (MID) AF: 0.00279 AC: 16 AN: 5732

European-Non Finnish (NFE) AF: 0.0201 AC: 22331 AN: 1110368

Other (OTH) AF: 0.0156 AC: 938 AN: 60198

GnomAD4 genome AF: 0.0117 AC: 1781 AN: 152190 Hom.: 13 Cov.: 32 AF XY: 0.0117 AC XY: 868 AN XY: 74386

African (AFR) AF: 0.00311 AC: 129 AN: 41528

American (AMR) AF: 0.00634 AC: 97 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00634 AC: 22 AN: 3470

East Asian (EAS) AF: 0.00792 AC: 41 AN: 5174

South Asian (SAS) AF: 0.00705 AC: 34 AN: 4820

European-Finnish (FIN) AF: 0.0193 AC: 205 AN: 10610

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0182 AC: 1240 AN: 67964

Other (OTH) AF: 0.00568 AC: 12 AN: 2114

Alfa AF: 0.0134 Hom.: 1

Bravo AF: 0.0106

TwinsUK AF: 0.0183 AC: 68

ALSPAC AF: 0.0153 AC: 59

ESP6500AA AF: 0.00303 AC: 13

ESP6500EA AF: 0.0169 AC: 141

ExAC AF: 0.0152 AC: 1834

Asia WGS AF: 0.00722 AC: 25 AN: 3478

EpiCase AF: 0.0159

EpiControl AF: 0.0138

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Nov 07, 2024

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

See Variant Classification Assertion Criteria.

TWIST1-related craniosynostosis Benign:1

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.73
CADD	Benign	5.7
DANN	Benign	0.96
DEOGEN2	Benign	0.098	T
Eigen	Benign	-0.99
Eigen_PC	Benign	-0.88
FATHMM_MKL	Benign	0.25	N
LIST_S2	Benign	0.62	T
MetaRNN	Benign	0.0027	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.34	N
PhyloP100		-0.035
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	0.11	N
REVEL	Benign	0.071
Sift	Benign	0.36	T
Sift4G	Benign	0.78	T
Polyphen		0.0010	B
Vest4		0.020
MPC		0.63
ClinPred		0.0038	T
GERP RS		2.9
Varity_R		0.031
gMVP		0.11
Mutation Taster		=97/3	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: rs139842507; hg19: chr19-42753020; COSMIC: COSV55897221; COSMIC: COSV55897221;