chr11-13694934-G-A

Position:

• chr11-13694934-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_032228.6(FAR1):​c.169G>A​(p.Glu57Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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: 32)
• Consequence: FAR1 NM_032228.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.46

Genes affected

FAR1 (HGNC:26222): (fatty acyl-CoA reductase 1) The protein encoded by this gene is required for the reduction of fatty acids to fatty alcohols, a process that is required for the synthesis of monoesters and ether lipids. NADPH is required as a cofactor in this reaction, and 16-18 carbon saturated and unsaturated fatty acids are the preferred substrate. This is a peroxisomal membrane protein, and studies suggest that the N-terminus contains a large catalytic domain located on the outside of the peroxisome, while the C-terminus is exposed to the matrix of the peroxisome. Studies indicate that the regulation of this protein is dependent on plasmalogen levels. Mutations in this gene have been associated with individuals affected by severe intellectual disability, early-onset epilepsy, microcephaly, congenital cataracts, growth retardation, and spasticity (PMID: 25439727). A pseudogene of this gene is located on chromosome 13. [provided by RefSeq, Jan 2015]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), FAR1. . Gene score misZ 3.3033 (greater than the threshold 3.09). Trascript score misZ 3.7056 (greater than threshold 3.09). GenCC has associacion of gene with fatty acyl-CoA reductase 1 deficiency, spastic paraparesis-cataracts-speech delay syndrome, hereditary spastic paraplegia 9A, fatty acyl-CoA reductase 1 upregulation.
• BP4: Computational evidence support a benign effect (MetaRNN=0.17733344).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FAR1	NM_032228.6	c.169G>A	p.Glu57Lys	missense_variant	2/12	ENST00000354817.8	NP_115604.1
FAR1	XM_011520400.3	c.169G>A	p.Glu57Lys	missense_variant	2/12		XP_011518702.1
FAR1	XM_047427690.1	c.169G>A	p.Glu57Lys	missense_variant	2/9		XP_047283646.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FAR1	ENST00000354817.8	c.169G>A	p.Glu57Lys	missense_variant	2/12	1	NM_032228.6	ENSP00000346874	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Mar 19, 2022

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 57 of the FAR1 protein (p.Glu57Lys). 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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. This variant has not been reported in the literature in individuals affected with FAR1-related conditions. This variant is not present in population databases (gnomAD no frequency). -

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	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Benign	0.021	T;.
Eigen	Benign	-0.20
Eigen_PC	Benign	0.045
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.87	D;D
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.18	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.99	L;.
MutationTaster	Benign	0.83	D
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-0.77	N;N
REVEL	Benign	0.075
Sift	Benign	0.73	T;T
Sift4G	Benign	0.82	T;T
Polyphen		0.0030	B;.
Vest4		0.28
MutPred		0.55		Gain of ubiquitination at E57 (P = 0.0192);Gain of ubiquitination at E57 (P = 0.0192);
MVP		0.53
MPC		1.0
ClinPred		0.77	D
GERP RS		5.6
Varity_R		0.35
gMVP		0.35

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: rs1848291417; hg19: chr11-13716481; COSMIC: COSV100701533;