rs1049951

Variant names:

• chr10-133370622-G-A
• rs1049951
• NM_004092.4:c.224C>T

Your query was ambiguous. Multiple possible variants found:

• chr10-133370622-G-A
• chr10-133370622-G-C

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 3P and 20B. PM1 PP2 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. 16/21 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:4
• Conservation: PhyloP100: 1.05
• Publications: 40 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: ClinGen, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• Leigh syndrome with leukodystrophy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -17 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, 7 uncertain in NM_004092.4
• 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=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 VariationId is 379965.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.957 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004092.4. 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
	ECHS1	NM_004092.4	MANE Select	c.224C>T	p.Thr75Ile	missense	Exon 2 of 8	NP_004083.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ECHS1	ENST00000368547.4	TSL:1 MANE Select	c.224C>T	p.Thr75Ile	missense	Exon 2 of 8	ENSP00000357535.3	P30084
	ECHS1	ENST00000857570.1		c.440C>T	p.Thr147Ile	missense	Exon 3 of 9	ENSP00000527629.1
	ECHS1	ENST00000970368.1		c.407C>T	p.Thr136Ile	missense	Exon 3 of 9	ENSP00000640427.1

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

GnomAD2 exomes AF: 0.919 AC: 228032 AN: 248164 AF XY: 0.926

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 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

African (AFR) AF: 0.519 AC: 17348 AN: 33446

American (AMR) AF: 0.943 AC: 42018 AN: 44568

Ashkenazi Jewish (ASJ) AF: 0.895 AC: 23346 AN: 26088

East Asian (EAS) AF: 0.976 AC: 38722 AN: 39670

South Asian (SAS) AF: 0.932 AC: 80214 AN: 86066

European-Finnish (FIN) AF: 0.972 AC: 50972 AN: 52440

Middle Eastern (MID) AF: 0.889 AC: 5127 AN: 5764

European-Non Finnish (NFE) AF: 0.946 AC: 1051080 AN: 1111468

Other (OTH) AF: 0.913 AC: 55088 AN: 60332

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

African (AFR) AF: 0.530 AC: 22013 AN: 41514

American (AMR) AF: 0.911 AC: 13951 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.890 AC: 3091 AN: 3472

East Asian (EAS) AF: 0.979 AC: 5070 AN: 5178

South Asian (SAS) AF: 0.932 AC: 4503 AN: 4832

European-Finnish (FIN) AF: 0.972 AC: 10325 AN: 10626

Middle Eastern (MID) AF: 0.878 AC: 258 AN: 294

European-Non Finnish (NFE) AF: 0.944 AC: 64241 AN: 68042

Other (OTH) AF: 0.865 AC: 1831 AN: 2116

Alfa AF: 0.910 Hom.: 255498

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Mitochondrial short-chain Enoyl-Coa hydratase 1 deficiency (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		1.1
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
Mutation Taster		=96/4	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: rs1049951; hg19: chr10-135184126; COSMIC: COSV107472237; COSMIC: COSV107472237;