rs377622362

Variant names:

• chr21-38423558-G-C
• rs377622362
• NM_182918.4:c.240C>G

Your query was ambiguous. Multiple possible variants found:

• chr21-38423558-G-C
• chr21-38423558-G-T

Variant summary

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

The NM_001136154.1(ERG):​c.261C>G​(p.Asn87Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 1,453,624 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: ERG NM_001136154.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.54
• Publications: 1 publications found

Genes affected

ERG (HGNC:3446): (ETS transcription factor ERG) This gene encodes a member of the erythroblast transformation-specific (ETS) family of transcriptions factors. All members of this family are key regulators of embryonic development, cell proliferation, differentiation, angiogenesis, inflammation, and apoptosis. The protein encoded by this gene is mainly expressed in the nucleus. It contains an ETS DNA-binding domain and a PNT (pointed) domain which is implicated in the self-association of chimeric oncoproteins. This protein is required for platelet adhesion to the subendothelium, inducing vascular cell remodeling. It also regulates hematopoesis, and the differentiation and maturation of megakaryocytic cells. This gene is involved in chromosomal translocations, resulting in different fusion gene products, such as TMPSSR2-ERG and NDRG1-ERG in prostate cancer, EWS-ERG in Ewing's sarcoma and FUS-ERG in acute myeloid leukemia. More than two dozens of transcript variants generated from combinatorial usage of three alternative promoters and multiple alternative splicing events have been reported, but the full-length nature of many of these variants has not been determined. [provided by RefSeq, Apr 2014]

ERG Gene-Disease associations (from GenCC):

• lymphatic malformation 14

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001136154.1. 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
	ERG	NM_182918.4	MANE Select	c.240C>G	p.Asn80Lys	missense	Exon 3 of 10	NP_891548.1
	ERG	NM_001136154.1		c.261C>G	p.Asn87Lys	missense	Exon 5 of 12	NP_001129626.1
	ERG	NM_001243428.1		c.261C>G	p.Asn87Lys	missense	Exon 5 of 12	NP_001230357.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ERG	ENST00000288319.12	TSL:1 MANE Select	c.240C>G	p.Asn80Lys	missense	Exon 3 of 10	ENSP00000288319.7
	ERG	ENST00000398919.6	TSL:1	c.261C>G	p.Asn87Lys	missense	Exon 5 of 12	ENSP00000381891.2
	ERG	ENST00000398905.5	TSL:1	c.240C>G	p.Asn80Lys	missense	Exon 3 of 9	ENSP00000381877.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000121 AC: 3 AN: 248244 AF XY: 0.0000149

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000463

Gnomad NFE exome AF: 0.00000889

Gnomad OTH exome AF: 0.000166

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1453624 Hom.: 0 Cov.: 30 AF XY: 0.00000139 AC XY: 1 AN XY: 721978

African (AFR) AF: 0.00 AC: 0 AN: 33258

American (AMR) AF: 0.00 AC: 0 AN: 43852

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25852

East Asian (EAS) AF: 0.00 AC: 0 AN: 39514

South Asian (SAS) AF: 0.00 AC: 0 AN: 85786

European-Finnish (FIN) AF: 0.0000375 AC: 2 AN: 53332

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5734

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1106346

Other (OTH) AF: 0.0000167 AC: 1 AN: 59950

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.20	T
Eigen	Benign	-0.10
Eigen_PC	Benign	0.020
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.23	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.3	L
PhyloP100		2.5
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-0.53	N
REVEL	Benign	0.022
Sift	Uncertain	0.019	D
Sift4G	Uncertain	0.054	T
Polyphen		0.043	B
Vest4		0.47
MutPred		0.26		Gain of ubiquitination at N87 (P = 7e-04)
MVP		0.62
MPC		0.24
ClinPred		0.30	T
GERP RS		5.2
Varity_R		0.11
gMVP		0.33
Mutation Taster		=238/62	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.28		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.28		Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs377622362; hg19: chr21-39795480;