10-11742661-C-T

Variant names:

• chr10-11742661-C-T
• rs1471937421
• NM_024693.5:c.85C>T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_024693.5(ECHDC3):​c.85C>T​(p.Arg29Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00001 in 1,098,558 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000010 (0 hom.)
• Consequence: ECHDC3 NM_024693.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0630

Genes affected

ECHDC3 (HGNC:23489): (enoyl-CoA hydratase domain containing 3) Predicted to enable enoyl-CoA hydratase activity. Involved in positive regulation of cellular response to insulin stimulus. Predicted to be active in mitochondrion. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.16142467).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ECHDC3	NM_024693.5	c.85C>T	p.Arg29Cys	missense_variant	Exon 1 of 5	ENST00000379215.9	NP_078969.3
ECHDC3	XM_047425750.1	c.85C>T	p.Arg29Cys	missense_variant	Exon 1 of 5		XP_047281706.1
ECHDC3	XM_011519689.1	c.85C>T	p.Arg29Cys	missense_variant	Exon 1 of 4		XP_011517991.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ECHDC3	ENST00000379215.9	c.85C>T	p.Arg29Cys	missense_variant	Exon 1 of 5	1	NM_024693.5	ENSP00000368517.4
ECHDC3	ENST00000496136.5	n.296C>T		non_coding_transcript_exon_variant	Exon 1 of 6	1
ECHDC3	ENST00000420401.5	c.85C>T	p.Arg29Cys	missense_variant	Exon 1 of 4	2		ENSP00000405584.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.0000100 AC: 11 AN: 1098558 Hom.: 0 Cov.: 31 AF XY: 0.0000134 AC XY: 7 AN XY: 523436

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000118

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 20, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.85C>T (p.R29C) alteration is located in exon 1 (coding exon 1) of the ECHDC3 gene. This alteration results from a C to T substitution at nucleotide position 85, causing the arginine (R) at amino acid position 29 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	16
DANN	Uncertain	0.99
DEOGEN2	Benign	0.063	T;T
Eigen	Benign	-0.75
Eigen_PC	Benign	-0.87
FATHMM_MKL	Benign	0.015	N
LIST_S2	Benign	0.62	T;T
M_CAP	Pathogenic	0.59	D
MetaRNN	Benign	0.16	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.69	N;.
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-0.64	N;N
REVEL	Benign	0.083
Sift	Benign	0.059	T;D
Sift4G	Benign	0.086	T;D
Polyphen		0.95	P;.
Vest4		0.13
MutPred		0.36		Loss of MoRF binding (P = 5e-04);Loss of MoRF binding (P = 5e-04);
MVP		0.32
MPC		0.16
ClinPred		0.42	T
GERP RS		-0.43
Varity_R		0.069
gMVP		0.52

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: rs1471937421; hg19: chr10-11784660;