rs139842507

Positions:

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

Variant summary

Our verdict is Benign. Variant got -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. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar 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

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]

ACMG classification

Verdict is Benign. Variant got -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 [Likely_benign]. Clinvar id is 476625.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-42248868-G-A is described in Lovd as [Likely_benign].
• 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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1781 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ERF	NM_006494.4	c.1244C>T	p.Ala415Val	missense_variant	4/4	ENST00000222329.9	NP_006485.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ERF	ENST00000222329.9	c.1244C>T	p.Ala415Val	missense_variant	4/4	1	NM_006494.4	ENSP00000222329	P1
ERF	ENST00000440177.6	c.1019C>T	p.Ala340Val	missense_variant	4/4	2		ENSP00000388173

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

GnomAD3 exomes AF: 0.0140 AC: 3275 AN: 233218 Hom.: 34 AF XY: 0.0142 AC XY: 1824 AN XY: 128496

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 SAS exome AF: 0.00974

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

Gnomad4 AFR exome AF: 0.00287

Gnomad4 AMR exome AF: 0.00586

Gnomad4 ASJ exome AF: 0.00658

Gnomad4 EAS exome AF: 0.0136

Gnomad4 SAS exome AF: 0.00982

Gnomad4 FIN exome AF: 0.0191

Gnomad4 NFE exome AF: 0.0201

Gnomad4 OTH exome AF: 0.0156

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

Gnomad4 AFR AF: 0.00311

Gnomad4 AMR AF: 0.00634

Gnomad4 ASJ AF: 0.00634

Gnomad4 EAS AF: 0.00792

Gnomad4 SAS AF: 0.00705

Gnomad4 FIN AF: 0.0193

Gnomad4 NFE AF: 0.0182

Gnomad4 OTH AF: 0.00568

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

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 24, 2023	See Variant Classification Assertion Criteria. -

TWIST1-related craniosynostosis Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 04, 2024

- -

Computational scores

Source: dbNSFP v4.3

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;T
MetaRNN	Benign	0.0027	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.34	N;.
MutationTaster	Benign	0.97	N;N
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	0.11	N;N
REVEL	Benign	0.071
Sift	Benign	0.36	T;T
Sift4G	Benign	0.78	T;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

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

Publications

LitVar

Other links and lift over

dbSNP: rs139842507; hg19: chr19-42753020; COSMIC: COSV55897221; COSMIC: COSV55897221;