chr13-77919605-C-T

Variant names:

• chr13-77919605-C-T
• rs201115708
• ENST00000377211.8:c.11G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The ENST00000377211.8(EDNRB):​c.11G>A​(p.Ser4Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000344 in 1,454,302 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S4T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: EDNRB ENST00000377211.8 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.27
• 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]

OBI1-AS1 (HGNC:42700): (OBI1 antisense RNA 1)

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.20235735).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EDNRB	NM_001201397.2	c.11G>A	p.Ser4Asn	missense_variant	Exon 1 of 8		NP_001188326.1
EDNRB	NM_000115.5	c.-51-981G>A		intron_variant	Intron 1 of 7		NP_000106.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EDNRB	ENST00000377211.8	c.11G>A	p.Ser4Asn	missense_variant	Exon 1 of 8	1		ENSP00000366416.4
EDNRB	ENST00000646948.1	c.-51-981G>A		intron_variant	Intron 1 of 7			ENSP00000493895.1
OBI1-AS1	ENST00000607862.5	n.-84C>T		upstream_gene_variant		1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000344 AC: 5 AN: 1454302 Hom.: 0 Cov.: 30 AF XY: 0.00000415 AC XY: 3 AN XY: 722070

African (AFR) AF: 0.00 AC: 0 AN: 33380

American (AMR) AF: 0.00 AC: 0 AN: 44508

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26040

East Asian (EAS) AF: 0.00 AC: 0 AN: 39474

South Asian (SAS) AF: 0.00 AC: 0 AN: 85938

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52202

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5752

European-Non Finnish (NFE) AF: 0.00000361 AC: 4 AN: 1106950

Other (OTH) AF: 0.0000167 AC: 1 AN: 60058

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	18
DANN	Uncertain	0.99
Eigen	Uncertain	0.21
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Benign	0.48	N
LIST_S2	Benign	0.29	T
M_CAP	Benign	0.051	D
MetaRNN	Benign	0.20	T
MetaSVM	Uncertain	0.043	D
PhyloP100		1.3
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-0.020	N
REVEL	Benign	0.21
Sift	Pathogenic	0.0	D
Vest4		0.22
MutPred		0.12		Gain of methylation at K3 (P = 0.0787);
MVP		0.67
MPC		0.45
ClinPred		1.0	D
GERP RS		4.3
PromoterAI		0.057	Neutral
gMVP		0.078
Mutation Taster		=81/19	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs201115708; hg19: chr13-78493740;