rs1049951

chr10-133370622-G-Achr10-133370622-G-C

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BA1

The NM_004092.4(ECHS1):c.224C>T(p.Thr75Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.924 in 1,612,138 control chromosomes in the GnomAD database, including 695,367 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T75S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.83 (54825 hom., cov: 35)
  • Exomes 𝑓: 0.93 (640542 hom.)
• Consequence: ECHS1 NM_004092.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.05

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]

ACMG classification

Verdict is Benign. Variant got -18 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_004092.4
• BP4: Computational evidence support a benign effect (MetaRNN=7.3618094E-7).
• BP6: Variant 10-133370622-G-A is Benign according to our data. Variant chr10-133370622-G-A is described in ClinVar as [Benign]. Clinvar id is 379965.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-133370622-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.957 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ECHS1	NM_004092.4	c.224C>T	p.Thr75Ile	missense_variant	2/8	ENST00000368547.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ECHS1	ENST00000368547.4	c.224C>T	p.Thr75Ile	missense_variant	2/8	1	NM_004092.4	P1

Frequencies

GnomAD3 genomes AF: 0.828 AC: 126054 AN: 152178 Hom.: 54810 Cov.: 35

Gnomad AFR AF: 0.531

Gnomad AMI AF: 0.897

Gnomad AMR AF: 0.911

Gnomad ASJ AF: 0.890

Gnomad EAS AF: 0.979

Gnomad SAS AF: 0.931

Gnomad FIN AF: 0.972

Gnomad MID AF: 0.883

Gnomad NFE AF: 0.944

Gnomad OTH AF: 0.864

GnomAD3 exomes AF: 0.919 AC: 228032 AN: 248164 Hom.: 106241 AF XY: 0.926 AC XY: 124624 AN XY: 134650

Gnomad AFR exome AF: 0.517

Gnomad AMR exome AF: 0.946

Gnomad ASJ exome AF: 0.893

Gnomad EAS exome AF: 0.975

Gnomad SAS exome AF: 0.933

Gnomad FIN exome AF: 0.973

Gnomad NFE exome AF: 0.946

Gnomad OTH exome AF: 0.927

GnomAD4 exome AF: 0.934 AC: 1363915 AN: 1459842 Hom.: 640542 Cov.: 70 AF XY: 0.935 AC XY: 679258 AN XY: 726128

Gnomad4 AFR exome AF: 0.519

Gnomad4 AMR exome AF: 0.943

Gnomad4 ASJ exome AF: 0.895

Gnomad4 EAS exome AF: 0.976

Gnomad4 SAS exome AF: 0.932

Gnomad4 FIN exome AF: 0.972

Gnomad4 NFE exome AF: 0.946

Gnomad4 OTH exome AF: 0.913

GnomAD4 genome AF: 0.828 AC: 126101 AN: 152296 Hom.: 54825 Cov.: 35 AF XY: 0.834 AC XY: 62084 AN XY: 74472

Gnomad4 AFR AF: 0.530

Gnomad4 AMR AF: 0.911

Gnomad4 ASJ AF: 0.890

Gnomad4 EAS AF: 0.979

Gnomad4 SAS AF: 0.932

Gnomad4 FIN AF: 0.972

Gnomad4 NFE AF: 0.944

Gnomad4 OTH AF: 0.865

Alfa AF: 0.923 Hom.: 130034

Bravo AF: 0.809

TwinsUK AF: 0.938 AC: 3478

ALSPAC AF: 0.944 AC: 3640

ESP6500AA AF: 0.530 AC: 2335

ESP6500EA AF: 0.940 AC: 8084

ExAC AF: 0.910 AC: 110057

Asia WGS AF: 0.930 AC: 3233 AN: 3478

EpiCase AF: 0.943

EpiControl AF: 0.942

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Dec 02, 2015

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Mitochondrial short-chain Enoyl-Coa hydratase 1 deficiency Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 30, 2021

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.60
Cadd	Benign	12
Dann	Benign	0.95
DEOGEN2	Benign	0.075	T
Eigen	Benign	-0.64
Eigen_PC	Benign	-0.55
FATHMM_MKL	Benign	0.59	D
LIST_S2	Benign	0.67	T
MetaRNN	Benign	7.4e-7	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.99	L
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.097
Sift	Benign	0.15	T
Sift4G	Benign	0.14	T
Polyphen		0.040	B
Vest4		0.033
MPC		0.49
ClinPred		0.0073	T
GERP RS		3.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.046
gMVP		0.48

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: rs1049951; hg19: chr10-135184126;