rs724159963

Variant names:

• chr11-13714647-A-G
• rs724159963
• NM_032228.6:c.1094A>G

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2 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. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Synonymous variant affecting the same amino acid position (i.e. D365D) has been classified as Likely benign.

• 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
• Publications: 4 publications found

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 Gene-Disease associations (from GenCC):

• fatty acyl-CoA reductase 1 deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, ClinGen, G2P, Labcorp Genetics (formerly Invitae), Orphanet
• spastic paraparesis-cataracts-speech delay syndrome

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• fatty acyl-CoA reductase 1 upregulation

  Inheritance: AD Classification: MODERATE Submitted by: ClinGen
• hereditary spastic paraplegia 9A

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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 VariationId is 162214.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032228.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FAR1	NM_032228.6	MANE Select	c.1094A>G	p.Asp365Gly	missense	Exon 9 of 12	NP_115604.1	Q8WVX9
	FAR1	NM_001441242.1		c.1103A>G	p.Asp368Gly	missense	Exon 9 of 12	NP_001428171.1
	FAR1	NM_001441244.1		c.1049A>G	p.Asp350Gly	missense	Exon 8 of 11	NP_001428173.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FAR1	ENST00000354817.8	TSL:1 MANE Select	c.1094A>G	p.Asp365Gly	missense	Exon 9 of 12	ENSP00000346874.3	Q8WVX9
	FAR1	ENST00000907330.1		c.1103A>G	p.Asp368Gly	missense	Exon 9 of 12	ENSP00000577389.1
	FAR1	ENST00000907331.1		c.1103A>G	p.Asp368Gly	missense	Exon 10 of 13	ENSP00000577390.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Fatty acyl-CoA reductase 1 deficiency (1)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		9.3
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
Mutation Taster		=8/92	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs724159963; hg19: chr11-13736194;