19-42248996-GGAAGAAGAA-GGAAGAA

Variant names:

• chr19-42248996-GGAA-G
• rs199960550
• NM_006494.4:c.1113_1115delTTC

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP3 BP6_Very_Strong BS1 BS2

The NM_006494.4(ERF):​c.1113_1115delTTC​(p.Ser372del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000255 in 1,609,182 control chromosomes in the GnomAD database, including 2 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00034 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00025 (1 hom.)
• Consequence: ERF NM_006494.4 disruptive_inframe_deletion
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 3.29
• 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: 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 -17 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_006494.4
• BP6: Variant 19-42248996-GGAA-G is Benign according to our data. Variant chr19-42248996-GGAA-G is described in ClinVar as Likely_benign. ClinVar VariationId is 476624.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000341 (52/152314) while in subpopulation EAS AF = 0.0027 (14/5188). AF 95% confidence interval is 0.00163. There are 1 homozygotes in GnomAd4. There are 21 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 52 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.1113_1115delTTC	p.Ser372del	disruptive_inframe_deletion	Exon 4 of 4	NP_006485.2
	ERF	NM_001301035.2		c.888_890delTTC	p.Ser297del	disruptive_inframe_deletion	Exon 4 of 4	NP_001287964.1
	ERF	NM_001308402.2		c.888_890delTTC	p.Ser297del	disruptive_inframe_deletion	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.1113_1115delTTC	p.Ser372del	disruptive_inframe_deletion	Exon 4 of 4	ENSP00000222329.3
	ENSG00000268643	ENST00000594664.1	TSL:3	c.22+5979_22+5981delTTC		intron	N/A	ENSP00000470087.1
	ERF	ENST00000440177.6	TSL:2	c.888_890delTTC	p.Ser297del	disruptive_inframe_deletion	Exon 4 of 4	ENSP00000388173.2

Frequencies

GnomAD3 genomes AF: 0.000342 AC: 52 AN: 152196 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000410

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00269

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000235

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000466 AC: 111 AN: 238320 AF XY: 0.000437

Gnomad AFR exome AF: 0.000415

Gnomad AMR exome AF: 0.000234

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00343

Gnomad FIN exome AF: 0.000268

Gnomad NFE exome AF: 0.000215

Gnomad OTH exome AF: 0.000682

GnomAD4 exome AF: 0.000246 AC: 358 AN: 1456868 Hom.: 1 AF XY: 0.000258 AC XY: 187 AN XY: 724620

African (AFR) AF: 0.000389 AC: 13 AN: 33458

American (AMR) AF: 0.000179 AC: 8 AN: 44676

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26102

East Asian (EAS) AF: 0.00209 AC: 83 AN: 39672

South Asian (SAS) AF: 0.000209 AC: 18 AN: 86210

European-Finnish (FIN) AF: 0.000202 AC: 10 AN: 49456

Middle Eastern (MID) AF: 0.000868 AC: 5 AN: 5762

European-Non Finnish (NFE) AF: 0.000154 AC: 171 AN: 1111214

Other (OTH) AF: 0.000812 AC: 49 AN: 60318

GnomAD4 genome AF: 0.000341 AC: 52 AN: 152314 Hom.: 1 Cov.: 32 AF XY: 0.000282 AC XY: 21 AN XY: 74472

African (AFR) AF: 0.000409 AC: 17 AN: 41558

American (AMR) AF: 0.0000653 AC: 1 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00270 AC: 14 AN: 5188

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4826

European-Finnish (FIN) AF: 0.000188 AC: 2 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000235 AC: 16 AN: 68020

Other (OTH) AF: 0.000473 AC: 1 AN: 2116

Alfa AF: 0.000436 Hom.: 0

Bravo AF: 0.000359

EpiCase AF: 0.000164

EpiControl AF: 0.0000593

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

TWIST1-related craniosynostosis Benign:1

Oct 23, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:1

Jun 03, 2020

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.3
Mutation Taster		=68/32	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: rs199960550; hg19: chr19-42753148;