rs76105803

Variant names:

• chr19-42249008-A-G
• rs76105803
• NM_006494.4:c.1104T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_006494.4(ERF):​c.1104T>C​(p.Ser368Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00599 in 1,609,782 control chromosomes in the GnomAD database, including 428 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.030 (221 hom., cov: 32)
  • Exomes 𝑓: 0.0035 (207 hom.)
• Consequence: ERF NM_006494.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.617
• 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 19-42249008-A-G is Benign according to our data. Variant chr19-42249008-A-G is described in ClinVar as Benign. ClinVar VariationId is 476623.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.617 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0997 is higher than 0.05.

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.1104T>C	p.Ser368Ser	synonymous	Exon 4 of 4	NP_006485.2
	ERF	NM_001301035.2		c.879T>C	p.Ser293Ser	synonymous	Exon 4 of 4	NP_001287964.1
	ERF	NM_001308402.2		c.879T>C	p.Ser293Ser	synonymous	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.1104T>C	p.Ser368Ser	synonymous	Exon 4 of 4	ENSP00000222329.3
	ENSG00000268643	ENST00000594664.1	TSL:3	c.22+5970T>C		intron	N/A	ENSP00000470087.1
	ERF	ENST00000440177.6	TSL:2	c.879T>C	p.Ser293Ser	synonymous	Exon 4 of 4	ENSP00000388173.2

Frequencies

GnomAD3 genomes AF: 0.0300 AC: 4561 AN: 152142 Hom.: 218 Cov.: 32

Gnomad AFR AF: 0.102

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0149

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000764

Gnomad OTH AF: 0.0229

GnomAD2 exomes AF: 0.00799 AC: 1933 AN: 241796 AF XY: 0.00588

Gnomad AFR exome AF: 0.111

Gnomad AMR exome AF: 0.00562

Gnomad ASJ exome AF: 0.000914

Gnomad EAS exome AF: 0.0000561

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000635

Gnomad OTH exome AF: 0.00457

GnomAD4 exome AF: 0.00347 AC: 5059 AN: 1457522 Hom.: 207 Cov.: 34 AF XY: 0.00303 AC XY: 2197 AN XY: 724774

African (AFR) AF: 0.105 AC: 3527 AN: 33446

American (AMR) AF: 0.00676 AC: 302 AN: 44656

Ashkenazi Jewish (ASJ) AF: 0.000996 AC: 26 AN: 26100

East Asian (EAS) AF: 0.000126 AC: 5 AN: 39644

South Asian (SAS) AF: 0.000232 AC: 20 AN: 86180

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50682

Middle Eastern (MID) AF: 0.00451 AC: 26 AN: 5762

European-Non Finnish (NFE) AF: 0.000673 AC: 748 AN: 1110766

Other (OTH) AF: 0.00672 AC: 405 AN: 60286

GnomAD4 genome AF: 0.0301 AC: 4582 AN: 152260 Hom.: 221 Cov.: 32 AF XY: 0.0295 AC XY: 2198 AN XY: 74446

African (AFR) AF: 0.102 AC: 4248 AN: 41532

American (AMR) AF: 0.0148 AC: 227 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00173 AC: 6 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

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

European-Non Finnish (NFE) AF: 0.000765 AC: 52 AN: 68016

Other (OTH) AF: 0.0227 AC: 48 AN: 2114

Alfa AF: 0.0118 Hom.: 22

Bravo AF: 0.0355

Asia WGS AF: 0.00375 AC: 13 AN: 3478

EpiCase AF: 0.000763

EpiControl AF: 0.000771

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	TWIST1-related craniosynostosis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	4.2
DANN	Benign	0.60
PhyloP100		-0.62
Mutation Taster		=100/0	polymorphism (auto)

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: rs76105803; hg19: chr19-42753160; COSMIC: COSV55895179; COSMIC: COSV55895179;