chr1-21225324-C-T

Variant names:

• chr1-21225324-C-T
• rs367812436
• NM_001397.3:c.1966G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PP5_Moderate BP4 BS2_Supporting

The NM_001397.3(ECE1):​c.1966G>A​(p.Gly656Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000279 in 1,614,234 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency:
  • Genomes: 𝑓 0.000072 (1 hom., cov: 32)
  • Exomes 𝑓: 0.000023 (0 hom.)
• Consequence: ECE1 NM_001397.3 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 2.04

Genes affected

ECE1 (HGNC:3146): (endothelin converting enzyme 1) The protein encoded by this gene is involved in proteolytic processing of endothelin precursors to biologically active peptides. Mutations in this gene are associated with Hirschsprung disease, cardiac defects and autonomic dysfunction. Alternatively spliced transcript variants encoding different isoforms have been noted for this gene.[provided by RefSeq, Sep 2009]

ACMG classification

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

• PP5: Variant 1-21225324-C-T is Pathogenic according to our data. Variant chr1-21225324-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1172769.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.12090194). . Strength limited to SUPPORTING due to the PP5.
• BS2: High AC in GnomAd4 at 11 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ECE1	NM_001397.3	c.1966G>A	p.Gly656Arg	missense_variant	Exon 17 of 19	ENST00000374893.11	NP_001388.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ECE1	ENST00000374893.11	c.1966G>A	p.Gly656Arg	missense_variant	Exon 17 of 19	1	NM_001397.3	ENSP00000364028.6

Frequencies

GnomAD3 genomes AF: 0.0000723 AC: 11 AN: 152230 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000769

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000716 AC: 18 AN: 251324 AF XY: 0.0000589

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000707

Gnomad FIN exome AF: 0.0000924

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.0000233 AC: 34 AN: 1461886 Hom.: 0 Cov.: 32 AF XY: 0.0000206 AC XY: 15 AN XY: 727244

Gnomad4 AFR exome AF: 0.00 AC: 0 AN: 33480

Gnomad4 AMR exome AF: 0.00 AC: 0 AN: 44724

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 26136

Gnomad4 EAS exome AF: 0.000327 AC: 13 AN: 39698

Gnomad4 SAS exome AF: 0.00 AC: 0 AN: 86258

Gnomad4 FIN exome AF: 0.000243 AC: 13 AN: 53418

Gnomad4 NFE exome AF: 0.00000540 AC: 6 AN: 1112008

Gnomad4 Remaining exome AF: 0.0000331 AC: 2 AN: 60396

GnomAD4 genome AF: 0.0000722 AC: 11 AN: 152348 Hom.: 1 Cov.: 32 AF XY: 0.0000268 AC XY: 2 AN XY: 74504

Gnomad4 AFR AF: 0.000120 AC: 0.000120239 AN: 0.000120239

Gnomad4 AMR AF: 0.00 AC: 0 AN: 0

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.000771 AC: 0.00077101 AN: 0.00077101

Gnomad4 SAS AF: 0.00 AC: 0 AN: 0

Gnomad4 FIN AF: 0.0000941 AC: 0.0000941265 AN: 0.0000941265

Gnomad4 NFE AF: 0.0000147 AC: 0.0000146998 AN: 0.0000146998

Gnomad4 OTH AF: 0.00 AC: 0 AN: 0

Alfa AF: 0.0000529 Hom.: 0

Bravo AF: 0.0000264

ExAC AF: 0.0000659 AC: 8

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hirschsprung disease, cardiac defects, and autonomic dysfunction Pathogenic:1

Mar 06, 2021

The Laboratory of Genetics and Metabolism, Hunan Children’s Hospital

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Uncertain	-0.060
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.83	.;.;.;D;D;.
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.95	D;D;D;D;D;D
MetaRNN	Benign	0.12	T;T;T;T;T;T
MetaSVM	Uncertain	0.66	D
MutationAssessor	Pathogenic	3.3	.;.;.;M;.;.
PrimateAI	Uncertain	0.69	T
PROVEAN	Uncertain	-4.1	D;.;D;D;D;D
REVEL	Pathogenic	0.65
Sift	Uncertain	0.024	D;.;D;D;D;D
Sift4G	Uncertain	0.015	D;.;D;D;D;D
Polyphen		0.69, 0.88, 0.76, 0.44	.;.;P;P;P;B
Vest4		0.54
MutPred		0.70		.;.;.;Gain of solvent accessibility (P = 0.0674);Gain of solvent accessibility (P = 0.0674);.;
MVP		0.82
MPC		1.2
ClinPred		0.47	T
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.60
gMVP		0.59
Mutation Taster		=73/27	polymorphism

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

Publications

LitVar

Other links and lift over

dbSNP: rs367812436; hg19: chr1-21551817; COSMIC: COSV51663282; COSMIC: COSV51663282;