rs4604

Variant names:

• chr10-133362587-G-A
• rs4604
• NM_004092.4:c.*281C>T

Your query was ambiguous. Multiple possible variants found:

• chr10-133362587-G-A
• chr10-133362587-G-C
• chr10-133362587-G-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004092.4(ECHS1):​c.*281C>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 0.798 in 493,812 control chromosomes in the GnomAD database, including 162,587 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.72 (42776 hom., cov: 32)
  • Exomes 𝑓: 0.83 (119811 hom.)
• Consequence: ECHS1 NM_004092.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0250
• Publications: 15 publications found

Genes affected

ECHS1 (HGNC:3151): (enoyl-CoA hydratase, short chain 1) The protein encoded by this gene functions in the second step of the mitochondrial fatty acid beta-oxidation pathway. It catalyzes the hydration of 2-trans-enoyl-coenzyme A (CoA) intermediates to L-3-hydroxyacyl-CoAs. The gene product is a member of the hydratase/isomerase superfamily. It localizes to the mitochondrial matrix. Transcript variants utilizing alternative transcription initiation sites have been described in the literature. [provided by RefSeq, Jul 2008]

ECHS1 Gene-Disease associations (from GenCC):

• Leigh syndrome

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• mitochondrial short-chain Enoyl-Coa hydratase 1 deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, ClinGen, G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), PanelApp Australia
• Leigh syndrome with leukodystrophy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BP6: Variant 10-133362587-G-A is Benign according to our data. Variant chr10-133362587-G-A is described in ClinVar as Benign. ClinVar VariationId is 1265360.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.934 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ECHS1	NM_004092.4	c.*281C>T		3_prime_UTR_variant	Exon 8 of 8	ENST00000368547.4	NP_004083.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ECHS1	ENST00000368547.4	c.*281C>T		3_prime_UTR_variant	Exon 8 of 8	1	NM_004092.4	ENSP00000357535.3

Frequencies

GnomAD3 genomes AF: 0.721 AC: 109505 AN: 151878 Hom.: 42759 Cov.: 32

Gnomad AFR AF: 0.391

Gnomad AMI AF: 0.899

Gnomad AMR AF: 0.831

Gnomad ASJ AF: 0.785

Gnomad EAS AF: 0.956

Gnomad SAS AF: 0.818

Gnomad FIN AF: 0.907

Gnomad MID AF: 0.725

Gnomad NFE AF: 0.837

Gnomad OTH AF: 0.748

GnomAD4 exome AF: 0.833 AC: 284620 AN: 341816 Hom.: 119811 Cov.: 2 AF XY: 0.832 AC XY: 149330 AN XY: 179520

African (AFR) AF: 0.388 AC: 3874 AN: 9976

American (AMR) AF: 0.865 AC: 12068 AN: 13958

Ashkenazi Jewish (ASJ) AF: 0.792 AC: 8340 AN: 10534

East Asian (EAS) AF: 0.960 AC: 21657 AN: 22570

South Asian (SAS) AF: 0.812 AC: 30722 AN: 37820

European-Finnish (FIN) AF: 0.903 AC: 18985 AN: 21024

Middle Eastern (MID) AF: 0.729 AC: 1079 AN: 1480

European-Non Finnish (NFE) AF: 0.839 AC: 171853 AN: 204762

Other (OTH) AF: 0.815 AC: 16042 AN: 19692

GnomAD4 genome AF: 0.721 AC: 109544 AN: 151996 Hom.: 42776 Cov.: 32 AF XY: 0.728 AC XY: 54105 AN XY: 74284

African (AFR) AF: 0.390 AC: 16152 AN: 41396

American (AMR) AF: 0.832 AC: 12715 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.785 AC: 2726 AN: 3472

East Asian (EAS) AF: 0.956 AC: 4940 AN: 5168

South Asian (SAS) AF: 0.819 AC: 3934 AN: 4806

European-Finnish (FIN) AF: 0.907 AC: 9597 AN: 10584

Middle Eastern (MID) AF: 0.721 AC: 212 AN: 294

European-Non Finnish (NFE) AF: 0.837 AC: 56866 AN: 67974

Other (OTH) AF: 0.751 AC: 1584 AN: 2108

Alfa AF: 0.796 Hom.: 67954

Bravo AF: 0.700

Asia WGS AF: 0.859 AC: 2986 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Jun 14, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.22
DANN	Benign	0.58
PhyloP100		-0.025
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
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: rs4604; hg19: chr10-135176091;