chr13-77896433-G-A

Variant names:

• chr13-77896433-G-A
• rs3027092
• NM_001122659.3:c.*1767C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001122659.3(EDNRB):​c.*1767C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0136 in 1,554,920 control chromosomes in the GnomAD database, including 255 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.014 (44 hom., cov: 32)
  • Exomes 𝑓: 0.013 (211 hom.)
• Consequence: EDNRB NM_001122659.3 3_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.225
• Publications: 4 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 13-77896433-G-A is Benign according to our data. Variant chr13-77896433-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 226627.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 = 0.0144 (2197/152064) while in subpopulation EAS AF = 0.0259 (133/5138). AF 95% confidence interval is 0.0223. There are 44 homozygotes in GnomAd4. There are 1181 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 44 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.*1767C>T		3_prime_UTR	Exon 7 of 7	NP_001116131.1	P24530-1
	EDNRB	NM_001201397.2		c.*1767C>T		3_prime_UTR	Exon 8 of 8	NP_001188326.1	P24530-3
	EDNRB	NM_000115.5		c.*1767C>T		3_prime_UTR	Exon 8 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.*1767C>T		3_prime_UTR	Exon 7 of 7	ENSP00000493527.1	P24530-1
	EDNRB	ENST00000377211.8	TSL:1	c.*1767C>T		3_prime_UTR	Exon 8 of 8	ENSP00000366416.4	P24530-3
	EDNRB	ENST00000626030.1	TSL:1	c.*9C>T		3_prime_UTR	Exon 7 of 7	ENSP00000486202.1	P24530-2

Frequencies

GnomAD3 genomes AF: 0.0145 AC: 2197 AN: 151946 Hom.: 44 Cov.: 32

Gnomad AFR AF: 0.00200

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00926

Gnomad ASJ AF: 0.0109

Gnomad EAS AF: 0.0258

Gnomad SAS AF: 0.0156

Gnomad FIN AF: 0.0511

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0170

Gnomad OTH AF: 0.0134

GnomAD2 exomes AF: 0.0156 AC: 2636 AN: 169286 AF XY: 0.0158

Gnomad AFR exome AF: 0.00194

Gnomad AMR exome AF: 0.00498

Gnomad ASJ exome AF: 0.00975

Gnomad EAS exome AF: 0.0213

Gnomad FIN exome AF: 0.0490

Gnomad NFE exome AF: 0.0144

Gnomad OTH exome AF: 0.0114

GnomAD4 exome AF: 0.0135 AC: 18876 AN: 1402856 Hom.: 211 Cov.: 31 AF XY: 0.0138 AC XY: 9584 AN XY: 692584

African (AFR) AF: 0.00152 AC: 49 AN: 32156

American (AMR) AF: 0.00488 AC: 178 AN: 36494

Ashkenazi Jewish (ASJ) AF: 0.0101 AC: 256 AN: 25324

East Asian (EAS) AF: 0.0156 AC: 580 AN: 37194

South Asian (SAS) AF: 0.0135 AC: 1073 AN: 79444

European-Finnish (FIN) AF: 0.0426 AC: 2117 AN: 49708

Middle Eastern (MID) AF: 0.0111 AC: 45 AN: 4062

European-Non Finnish (NFE) AF: 0.0127 AC: 13755 AN: 1080534

Other (OTH) AF: 0.0142 AC: 823 AN: 57940

GnomAD4 genome AF: 0.0144 AC: 2197 AN: 152064 Hom.: 44 Cov.: 32 AF XY: 0.0159 AC XY: 1181 AN XY: 74322

African (AFR) AF: 0.00200 AC: 83 AN: 41522

American (AMR) AF: 0.00925 AC: 141 AN: 15242

Ashkenazi Jewish (ASJ) AF: 0.0109 AC: 38 AN: 3472

East Asian (EAS) AF: 0.0259 AC: 133 AN: 5138

South Asian (SAS) AF: 0.0156 AC: 75 AN: 4814

European-Finnish (FIN) AF: 0.0511 AC: 542 AN: 10606

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0170 AC: 1155 AN: 67952

Other (OTH) AF: 0.0133 AC: 28 AN: 2112

Alfa AF: 0.0130 Hom.: 19

Bravo AF: 0.00958

Asia WGS AF: 0.0250 AC: 87 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	1.6
DANN	Benign	0.28
PhyloP100		0.23
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: rs3027092; hg19: chr13-78470568; COSMIC: COSV57527714; COSMIC: COSV57527714;