NM_004826.4:c.*67A>T

Variant names:

• chr2-232480086-T-A
• rs114966878
• NM_004826.4:c.*67A>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_004826.4(ECEL1):​c.*67A>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 0.00223 in 1,510,460 control chromosomes in the GnomAD database, including 52 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 (37 hom., cov: 33)
  • Exomes 𝑓: 0.0013 (15 hom.)
• Consequence: ECEL1 NM_004826.4 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.449
• Publications: 2 publications found

Genes affected

ECEL1 (HGNC:3147): (endothelin converting enzyme like 1) This gene encodes a member of the M13 family of endopeptidases. Members of this family are zinc-containing type II integral-membrane proteins that are important regulators of neuropeptide and peptide hormone activity. Mutations in this gene are associated with autosomal recessive distal arthrogryposis, type 5D. This gene has multiple pseudogenes on chromosome 2. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Mar 2014]

ECEL1 Gene-Disease associations (from GenCC):

• distal arthrogryposis type 5D

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.31).
• BP6: Variant 2-232480086-T-A is Benign according to our data. Variant chr2-232480086-T-A is described in ClinVar as Likely_benign. ClinVar VariationId is 1208946.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 = 0.0106 (1610/152196) while in subpopulation AFR AF = 0.0366 (1521/41546). AF 95% confidence interval is 0.0351. There are 37 homozygotes in GnomAd4. There are 750 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 37 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004826.4. 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
	ECEL1	NM_004826.4	MANE Select	c.*67A>T		3_prime_UTR	Exon 18 of 18	NP_004817.2	A0A6F7YIA8
	ECEL1	NM_001290787.2		c.*67A>T		3_prime_UTR	Exon 18 of 18	NP_001277716.1	O95672-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ECEL1	ENST00000304546.6	TSL:1 MANE Select	c.*67A>T		3_prime_UTR	Exon 18 of 18	ENSP00000302051.1	O95672-1
	ECEL1	ENST00000862796.1		c.*67A>T		3_prime_UTR	Exon 18 of 18	ENSP00000532855.1
	ECEL1	ENST00000931992.1		c.*67A>T		3_prime_UTR	Exon 18 of 18	ENSP00000602051.1

Frequencies

GnomAD3 genomes AF: 0.0106 AC: 1608 AN: 152074 Hom.: 37 Cov.: 33

Gnomad AFR AF: 0.0367

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00373

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.00718

GnomAD4 exome AF: 0.00130 AC: 1760 AN: 1358264 Hom.: 15 Cov.: 24 AF XY: 0.00116 AC XY: 784 AN XY: 678092

African (AFR) AF: 0.0394 AC: 1235 AN: 31308

American (AMR) AF: 0.00235 AC: 101 AN: 43000

Ashkenazi Jewish (ASJ) AF: 0.000977 AC: 23 AN: 23550

East Asian (EAS) AF: 0.00 AC: 0 AN: 38356

South Asian (SAS) AF: 0.000111 AC: 9 AN: 81326

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51054

Middle Eastern (MID) AF: 0.00430 AC: 21 AN: 4886

European-Non Finnish (NFE) AF: 0.000225 AC: 231 AN: 1028526

Other (OTH) AF: 0.00249 AC: 140 AN: 56258

GnomAD4 genome AF: 0.0106 AC: 1610 AN: 152196 Hom.: 37 Cov.: 33 AF XY: 0.0101 AC XY: 750 AN XY: 74406

African (AFR) AF: 0.0366 AC: 1521 AN: 41546

American (AMR) AF: 0.00372 AC: 57 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5158

South Asian (SAS) AF: 0.00 AC: 0 AN: 4806

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000176 AC: 12 AN: 67990

Other (OTH) AF: 0.00711 AC: 15 AN: 2110

Alfa AF: 0.00807 Hom.: 0

Bravo AF: 0.0122

Asia WGS AF: 0.00260 AC: 9 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.31
CADD	Benign	11
DANN	Benign	0.87
PhyloP100		0.45
Mutation Taster		=100/0	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: rs114966878; hg19: chr2-233344796;