rs724159963

Positions:

• chr11-13714647-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PP2 PP3_Strong PP5

The NM_032228.6(FAR1):​c.1094A>G​(p.Asp365Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: FAR1 NM_032228.6 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 9.32

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 Likely_pathogenic. Variant got 8 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, 0.955
• PP5: Variant 11-13714647-A-G is Pathogenic according to our data. Variant chr11-13714647-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 162214.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FAR1	NM_032228.6	c.1094A>G	p.Asp365Gly	missense_variant	9/12	ENST00000354817.8	NP_115604.1
FAR1	XM_011520400.3	c.1103A>G	p.Asp368Gly	missense_variant	9/12		XP_011518702.1
FAR1	XM_047427690.1	c.965-329A>G		intron_variant			XP_047283646.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FAR1	ENST00000354817.8	c.1094A>G	p.Asp365Gly	missense_variant	9/12	1	NM_032228.6	ENSP00000346874	P1
FAR1	ENST00000527202.1	n.527A>G		non_coding_transcript_exon_variant	5/6	2
FAR1	ENST00000703358.1	c.956-329A>G		intron_variant, NMD_transcript_variant				ENSP00000515269

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Fatty acyl-CoA reductase 1 deficiency Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Nov 06, 2014

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.20
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.70	D
Eigen	Pathogenic	0.97
Eigen_PC	Pathogenic	0.91
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.18	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Benign	-0.30	T
MutationAssessor	Pathogenic	4.2	H
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-6.6	D
REVEL	Pathogenic	0.91
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.98
MutPred		0.75		Gain of helix (P = 0.0078);
MVP		0.88
MPC		2.3
ClinPred		1.0	D
GERP RS		5.6
Varity_R		0.95
gMVP		1.0

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: rs724159963; hg19: chr11-13736194;