11-13694777-C-T

Position:

• chr11-13694777-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_032228.6(FAR1):​c.12C>T​(p.Ile4=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0176 in 1,611,654 control chromosomes in the GnomAD database, including 320 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.013 (18 hom., cov: 32)
  • Exomes 𝑓: 0.018 (302 hom.)
• Consequence: FAR1 NM_032228.6 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.341

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 Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.3).
• BP6: Variant 11-13694777-C-T is Benign according to our data. Variant chr11-13694777-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 1320619.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.341 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0132 (2003/152236) while in subpopulation NFE AF= 0.0197 (1343/68004). AF 95% confidence interval is 0.0189. There are 18 homozygotes in gnomad4. There are 924 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 18 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FAR1	NM_032228.6	c.12C>T	p.Ile4=	synonymous_variant	2/12	ENST00000354817.8	NP_115604.1
FAR1	XM_011520400.3	c.12C>T	p.Ile4=	synonymous_variant	2/12		XP_011518702.1
FAR1	XM_047427690.1	c.12C>T	p.Ile4=	synonymous_variant	2/9		XP_047283646.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FAR1	ENST00000354817.8	c.12C>T	p.Ile4=	synonymous_variant	2/12	1	NM_032228.6	ENSP00000346874	P1
FAR1	ENST00000532701.1	c.12C>T	p.Ile4=	synonymous_variant	2/8	2		ENSP00000437111
FAR1	ENST00000532769.1	n.22C>T		non_coding_transcript_exon_variant	1/2	2
FAR1	ENST00000703358.1	c.12C>T	p.Ile4=	synonymous_variant, NMD_transcript_variant	1/11			ENSP00000515269

Frequencies

GnomAD3 genomes AF: 0.0132 AC: 2003 AN: 152118 Hom.: 18 Cov.: 32

Gnomad AFR AF: 0.00454

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0133

Gnomad ASJ AF: 0.0101

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0122

Gnomad FIN AF: 0.0108

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0198

Gnomad OTH AF: 0.0239

GnomAD3 exomes AF: 0.0149 AC: 3702 AN: 248780 Hom.: 48 AF XY: 0.0152 AC XY: 2038 AN XY: 134388

Gnomad AFR exome AF: 0.00407

Gnomad AMR exome AF: 0.0156

Gnomad ASJ exome AF: 0.0102

Gnomad EAS exome AF: 0.000218

Gnomad SAS exome AF: 0.0118

Gnomad FIN exome AF: 0.00948

Gnomad NFE exome AF: 0.0205

Gnomad OTH exome AF: 0.0217

GnomAD4 exome AF: 0.0180 AC: 26330 AN: 1459418 Hom.: 302 Cov.: 30 AF XY: 0.0180 AC XY: 13091 AN XY: 725954

Gnomad4 AFR exome AF: 0.00311

Gnomad4 AMR exome AF: 0.0150

Gnomad4 ASJ exome AF: 0.00955

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0119

Gnomad4 FIN exome AF: 0.0104

Gnomad4 NFE exome AF: 0.0203

Gnomad4 OTH exome AF: 0.0174

GnomAD4 genome AF: 0.0132 AC: 2003 AN: 152236 Hom.: 18 Cov.: 32 AF XY: 0.0124 AC XY: 924 AN XY: 74432

Gnomad4 AFR AF: 0.00452

Gnomad4 AMR AF: 0.0133

Gnomad4 ASJ AF: 0.0101

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0125

Gnomad4 FIN AF: 0.0108

Gnomad4 NFE AF: 0.0197

Gnomad4 OTH AF: 0.0237

Alfa AF: 0.0175 Hom.: 15

Bravo AF: 0.0132

Asia WGS AF: 0.00577 AC: 20 AN: 3478

EpiCase AF: 0.0183

EpiControl AF: 0.0205

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 11, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 05, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.30
CADD	Benign	10
DANN	Benign	0.74
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs117395380; hg19: chr11-13716324;