rs1057520096

Variant names:

• chr10-133373327-C-A
• rs1057520096
• NM_004092.4:c.7G>T

Your query was ambiguous. Multiple possible variants found:

• chr10-133373327-C-A
• chr10-133373327-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 7P and 2B. PM1 PM2 PM5 PP2 BP4_Moderate

The NM_004092.4(ECHS1):​c.7G>T​(p.Ala3Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000444 in 1,350,212 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 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. A3V) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000044 (0 hom.)
• Consequence: ECHS1 NM_004092.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.14
• Publications: 0 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: Uncertain_significance. The variant received 5 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 4 uncertain in NM_004092.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr10-133373326-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 692007.
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 35 curated pathogenic missense variants (we use a threshold of 10). The gene has 4 curated benign missense variants. Gene score misZ: 0.8627 (below the threshold of 3.09). Trascript score misZ: 0.70218 (below the threshold of 3.09). GenCC associations: The gene is linked to Leigh syndrome with leukodystrophy, Leigh syndrome, mitochondrial short-chain Enoyl-Coa hydratase 1 deficiency.
• BP4: Computational evidence support a benign effect (MetaRNN=0.12108505).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ECHS1	NM_004092.4	c.7G>T	p.Ala3Ser	missense_variant	Exon 1 of 8	ENST00000368547.4	NP_004083.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ECHS1	ENST00000368547.4	c.7G>T	p.Ala3Ser	missense_variant	Exon 1 of 8	1	NM_004092.4	ENSP00000357535.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000444 AC: 6 AN: 1350212 Hom.: 0 Cov.: 34 AF XY: 0.00000601 AC XY: 4 AN XY: 666056

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 27750

American (AMR) AF: 0.0000306 AC: 1 AN: 32720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23712

East Asian (EAS) AF: 0.00 AC: 0 AN: 30088

South Asian (SAS) AF: 0.0000130 AC: 1 AN: 76654

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 34590

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4558

European-Non Finnish (NFE) AF: 0.00000376 AC: 4 AN: 1063810

Other (OTH) AF: 0.00 AC: 0 AN: 56330

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0135741), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	4.1
DANN	Benign	0.83
DEOGEN2	Benign	0.022	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.0076	N
LIST_S2	Benign	0.39	T
M_CAP	Uncertain	0.22	D
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.81	L
PhyloP100		-1.1
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-0.57	N
REVEL	Benign	0.040
Sift	Uncertain	0.027	D
Sift4G	Benign	0.53	T
Polyphen		0.016	B
Vest4		0.19
MutPred		0.28		Gain of disorder (P = 0.0245);
MVP		0.58
MPC		0.42
ClinPred		0.12	T
GERP RS		-0.83
PromoterAI		-0.55	Under-expression
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.082
gMVP		0.72
Mutation Taster		=97/3	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

Other links and lift over

dbSNP: rs1057520096; hg19: chr10-135186831;