NM_001122659.3:c.*1632C>A

Variant names:

• chr13-77896568-G-T
• rs876657804
• NM_001122659.3:c.*1632C>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001122659.3(EDNRB):​c.*1632C>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000716 in 1,397,258 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: EDNRB NM_001122659.3 3_prime_UTR
• Scores: Splicing: ADA: 0.00001460
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.948
• Publications: 0 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EDNRB	NM_001122659.3	MANE Select	c.*1632C>A		3_prime_UTR	Exon 7 of 7	NP_001116131.1
	EDNRB	NM_001201397.2		c.*1632C>A		3_prime_UTR	Exon 8 of 8	NP_001188326.1
	EDNRB	NM_000115.5		c.*1632C>A		3_prime_UTR	Exon 8 of 8	NP_000106.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EDNRB	ENST00000646607.2	MANE Select	c.*1632C>A		3_prime_UTR	Exon 7 of 7	ENSP00000493527.1
	EDNRB	ENST00000377211.8	TSL:1	c.*1632C>A		3_prime_UTR	Exon 8 of 8	ENSP00000366416.4
	EDNRB	ENST00000626030.1	TSL:1	c.1195-10C>A		intron	N/A	ENSP00000486202.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000629 AC: 1 AN: 158902 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000414

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 7.16e-7 AC: 1 AN: 1397258 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 689376

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 31652

American (AMR) AF: 0.0000281 AC: 1 AN: 35578

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25302

East Asian (EAS) AF: 0.00 AC: 0 AN: 36270

South Asian (SAS) AF: 0.00 AC: 0 AN: 78978

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49132

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4332

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1078192

Other (OTH) AF: 0.00 AC: 0 AN: 57822

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.27
DANN	Benign	0.63
PhyloP100		-0.95

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000015
dbscSNV1_RF	Benign	0.0
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: rs876657804; hg19: chr13-78470703; COSMIC: COSV105890559; COSMIC: COSV105890559;