11-13694827-T-G

Position:

• chr11-13694827-T-G

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP2 PP3_Strong

The NM_032228.6(FAR1):​c.62T>G​(p.Phe21Cys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: FAR1 NM_032228.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.86

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]

FAR1 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.987

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FAR1	NM_032228.6	c.62T>G	p.Phe21Cys	missense_variant	2/12	ENST00000354817.8	NP_115604.1
FAR1	XM_011520400.3	c.62T>G	p.Phe21Cys	missense_variant	2/12		XP_011518702.1
FAR1	XM_047427690.1	c.62T>G	p.Phe21Cys	missense_variant	2/9		XP_047283646.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FAR1	ENST00000354817.8	c.62T>G	p.Phe21Cys	missense_variant	2/12	1	NM_032228.6	ENSP00000346874.3
FAR1	ENST00000532701.1	c.62T>G	p.Phe21Cys	missense_variant	2/8	2		ENSP00000437111.1
FAR1	ENST00000532769.1	n.72T>G		non_coding_transcript_exon_variant	1/2	2
FAR1	ENST00000703358.1	n.62T>G		non_coding_transcript_exon_variant	1/11			ENSP00000515269.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 08, 2024

The c.62T>G (p.F21C) alteration is located in exon 2 (coding exon 1) of the FAR1 gene. This alteration results from a T to G substitution at nucleotide position 62, causing the phenylalanine (F) at amino acid position 21 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	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.30
CADD	Pathogenic	32
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.44	T;.
Eigen	Pathogenic	0.98
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	1.0	D;D
M_CAP	Pathogenic	0.59	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Uncertain	0.54	D
MutationAssessor	Pathogenic	4.6	H;.
PrimateAI	Pathogenic	0.80	T
PROVEAN	Pathogenic	-7.1	D;D
REVEL	Pathogenic	0.88
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;.
Vest4		0.74
MutPred		0.89		Gain of methylation at K24 (P = 0.1729);Gain of methylation at K24 (P = 0.1729);
MVP		0.85
MPC		2.5
ClinPred		1.0	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.95
gMVP		0.92

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-13716374;