rs5349

Variant names:

• chr13-77903530-G-A
• rs5349
• NM_001122659.3:c.561C>T

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_001122659.3(EDNRB):​c.561C>T​(p.Ile187Ile) variant causes a synonymous change. The variant allele was found at a frequency of 0.00468 in 1,612,902 control chromosomes in the GnomAD database, including 64 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (23 hom., cov: 32)
  • Exomes 𝑓: 0.0040 (41 hom.)
• Consequence: EDNRB NM_001122659.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 3.84
• Publications: 8 publications found

Genes affected

EDNRB (HGNC:3180): (endothelin receptor type B) The protein encoded by this gene is a G protein-coupled receptor which activates a phosphatidylinositol-calcium second messenger system. Its ligand, endothelin, consists of a family of three potent vasoactive peptides: ET1, ET2, and ET3. Studies suggest that the multigenic disorder, Hirschsprung disease type 2, is due to mutations in the endothelin receptor type B gene. Alternative splicing and the use of alternative promoters results in multiple transcript variants. [provided by RefSeq, Oct 2016]

EDNRB-AS1 (HGNC:49045): (EDNRB antisense RNA 1)

ACMG classification

Our verdict: Benign. The variant received -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.29).
• BP6: Variant 13-77903530-G-A is Benign according to our data. Variant chr13-77903530-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 226626.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0108 (1643/152036) while in subpopulation AFR AF = 0.0282 (1171/41518). AF 95% confidence interval is 0.0269. There are 23 homozygotes in GnomAd4. There are 766 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 23 AD,AR,Unknown,SD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001122659.3. 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
	EDNRB	NM_001122659.3	MANE Select	c.561C>T	p.Ile187Ile	synonymous	Exon 2 of 7	NP_001116131.1	P24530-1
	EDNRB	NM_001201397.2		c.831C>T	p.Ile277Ile	synonymous	Exon 3 of 8	NP_001188326.1	P24530-3
	EDNRB	NM_000115.5		c.561C>T	p.Ile187Ile	synonymous	Exon 3 of 8	NP_000106.1	P24530-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EDNRB	ENST00000646607.2	MANE Select	c.561C>T	p.Ile187Ile	synonymous	Exon 2 of 7	ENSP00000493527.1	P24530-1
	EDNRB	ENST00000377211.8	TSL:1	c.831C>T	p.Ile277Ile	synonymous	Exon 3 of 8	ENSP00000366416.4	P24530-3
	EDNRB	ENST00000626030.1	TSL:1	c.561C>T	p.Ile187Ile	synonymous	Exon 2 of 7	ENSP00000486202.1	P24530-2

Frequencies

GnomAD3 genomes AF: 0.0108 AC: 1635 AN: 151918 Hom.: 22 Cov.: 32

Gnomad AFR AF: 0.0280

Gnomad AMI AF: 0.0121

Gnomad AMR AF: 0.00623

Gnomad ASJ AF: 0.0254

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.00358

Gnomad OTH AF: 0.0125

GnomAD2 exomes AF: 0.00548 AC: 1373 AN: 250324 AF XY: 0.00502

Gnomad AFR exome AF: 0.0289

Gnomad AMR exome AF: 0.00563

Gnomad ASJ exome AF: 0.0234

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.00370

Gnomad OTH exome AF: 0.00589

GnomAD4 exome AF: 0.00404 AC: 5903 AN: 1460866 Hom.: 41 Cov.: 31 AF XY: 0.00389 AC XY: 2830 AN XY: 726764

African (AFR) AF: 0.0316 AC: 1054 AN: 33404

American (AMR) AF: 0.00599 AC: 267 AN: 44594

Ashkenazi Jewish (ASJ) AF: 0.0227 AC: 591 AN: 26080

East Asian (EAS) AF: 0.00 AC: 0 AN: 39682

South Asian (SAS) AF: 0.000673 AC: 58 AN: 86238

European-Finnish (FIN) AF: 0.000225 AC: 12 AN: 53404

Middle Eastern (MID) AF: 0.0115 AC: 66 AN: 5754

European-Non Finnish (NFE) AF: 0.00310 AC: 3447 AN: 1111388

Other (OTH) AF: 0.00676 AC: 408 AN: 60322

GnomAD4 genome AF: 0.0108 AC: 1643 AN: 152036 Hom.: 23 Cov.: 32 AF XY: 0.0103 AC XY: 766 AN XY: 74306

African (AFR) AF: 0.0282 AC: 1171 AN: 41518

American (AMR) AF: 0.00623 AC: 95 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.0254 AC: 88 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5136

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4814

European-Finnish (FIN) AF: 0.0000942 AC: 1 AN: 10616

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.00358 AC: 243 AN: 67910

Other (OTH) AF: 0.0123 AC: 26 AN: 2110

Alfa AF: 0.00790 Hom.: 9

Bravo AF: 0.0121

Asia WGS AF: 0.00606 AC: 22 AN: 3478

EpiCase AF: 0.00442

EpiControl AF: 0.00551

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	not provided (3)
-	-	1	Hirschsprung disease, susceptibility to, 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.29
CADD	Benign	12
DANN	Benign	0.77
PhyloP100		3.8
PromoterAI		-0.016	Neutral
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs5349; hg19: chr13-78477665;