1-43364549-A-C

Variant names:

• chr1-43364549-A-C
• NM_022821.4:c.474T>G

Variant summary

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

The NM_022821.4(ELOVL1):​c.474T>G​(p.Ile158Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,852 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ELOVL1 NM_022821.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.39

Genes affected

ELOVL1 (HGNC:14418): (ELOVL fatty acid elongase 1) Enables fatty acid elongase activity. Involved in fatty acid biosynthetic process and sphingolipid biosynthetic process. Located in endoplasmic reticulum. [provided by Alliance of Genome Resources, Apr 2022]

MIR6734 (HGNC:50219): (microRNA 6734) microRNAs (miRNAs) are short (20-24 nt) non-coding RNAs that are involved in post-transcriptional regulation of gene expression in multicellular organisms by affecting both the stability and translation of mRNAs. miRNAs are transcribed by RNA polymerase II as part of capped and polyadenylated primary transcripts (pri-miRNAs) that can be either protein-coding or non-coding. The primary transcript is cleaved by the Drosha ribonuclease III enzyme to produce an approximately 70-nt stem-loop precursor miRNA (pre-miRNA), which is further cleaved by the cytoplasmic Dicer ribonuclease to generate the mature miRNA and antisense miRNA star (miRNA*) products. The mature miRNA is incorporated into a RNA-induced silencing complex (RISC), which recognizes target mRNAs through imperfect base pairing with the miRNA and most commonly results in translational inhibition or destabilization of the target mRNA. The RefSeq represents the predicted microRNA stem-loop. [provided by RefSeq, Sep 2009]

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=0.14483926).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ELOVL1	NM_022821.4	c.474T>G	p.Ile158Met	missense_variant	Exon 6 of 8	ENST00000372458.8	NP_073732.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ELOVL1	ENST00000372458.8	c.474T>G	p.Ile158Met	missense_variant	Exon 6 of 8	1	NM_022821.4	ENSP00000361536.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461852 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727234

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Apr 29, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt ELOVL1 protein function. This sequence change replaces isoleucine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 158 of the ELOVL1 protein (p.Ile158Met). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with ELOVL1-related conditions. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	20
DANN	Benign	0.96
DEOGEN2	Benign	0.013	T;T;.
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.14
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Uncertain	0.95	.;D;D
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.14	T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.63	N;N;.
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.27	N;.;N
REVEL	Benign	0.063
Sift	Uncertain	0.0010	D;.;D
Sift4G	Uncertain	0.0020	D;D;D
Polyphen		0.16	B;B;.
Vest4		0.22
MutPred		0.54		Gain of disorder (P = 0.0447);Gain of disorder (P = 0.0447);.;
MVP		0.34
MPC		0.98
ClinPred		0.35	T
GERP RS		1.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.22
gMVP		0.73

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-43830220;