rs727502796

Variant names:

• chr11-13708029-AGTAGTCTATCCA-T
• rs727502796
• NM_032228.6:c.495_507delAGTAGTCTATCCAinsT

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PM4 PP3 PP5_Moderate

The NM_032228.6(FAR1):​c.495_507delAGTAGTCTATCCAinsT​(p.Glu165_Pro169delinsAsp) variant causes a missense, conservative inframe deletion change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: FAR1 NM_032228.6 missense, conservative_inframe_deletion
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• 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 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_032228.6.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
• PP5: Variant 11-13708029-AGTAGTCTATCCA-T is Pathogenic according to our data. Variant chr11-13708029-AGTAGTCTATCCA-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 162212.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FAR1	NM_032228.6	c.495_507delAGTAGTCTATCCAinsT	p.Glu165_Pro169delinsAsp	missense_variant, conservative_inframe_deletion	Exon 4 of 12	ENST00000354817.8	NP_115604.1
FAR1	XM_011520400.3	c.495_507delAGTAGTCTATCCAinsT	p.Glu165_Pro169delinsAsp	missense_variant, conservative_inframe_deletion	Exon 4 of 12		XP_011518702.1
FAR1	XM_047427690.1	c.495_507delAGTAGTCTATCCAinsT	p.Glu165_Pro169delinsAsp	missense_variant, conservative_inframe_deletion	Exon 4 of 9		XP_047283646.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FAR1	ENST00000354817.8	c.495_507delAGTAGTCTATCCAinsT	p.Glu165_Pro169delinsAsp	missense_variant, conservative_inframe_deletion	Exon 4 of 12	1	NM_032228.6	ENSP00000346874.3
FAR1	ENST00000532701.1	c.495_507delAGTAGTCTATCCAinsT	p.Glu165_Pro169delinsAsp	missense_variant, conservative_inframe_deletion	Exon 4 of 8	2		ENSP00000437111.1
FAR1	ENST00000524933.1	n.361_373delAGTAGTCTATCCAinsT		non_coding_transcript_exon_variant	Exon 3 of 4	2
FAR1	ENST00000703358.1	n.495_507delAGTAGTCTATCCAinsT		non_coding_transcript_exon_variant	Exon 3 of 11			ENSP00000515269.1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Fatty acyl-CoA reductase 1 deficiency Pathogenic:2

May 08, 2023

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Review of the variants reported in Reuter et al., 2017, PMID: 28097321: PS3,PM4,PM3_Supporting,PM2 -

Nov 06, 2014

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs727502796; hg19: chr11-13729576;