11-13694635-G-A

Position:

• chr11-13694635-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_032228.6(FAR1):​c.-7-124G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0383 in 770,318 control chromosomes in the GnomAD database, including 719 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.032 (113 hom., cov: 32)
  • Exomes 𝑓: 0.040 (606 hom.)
• Consequence: FAR1 NM_032228.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.382

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 11-13694635-G-A is Benign according to our data. Variant chr11-13694635-G-A is described in ClinVar as [Benign]. Clinvar id is 1237394.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0322 (4895/152240) while in subpopulation NFE AF= 0.0469 (3190/67980). AF 95% confidence interval is 0.0456. There are 113 homozygotes in gnomad4. There are 2387 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 113 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FAR1	NM_032228.6	c.-7-124G>A		intron_variant		ENST00000354817.8	NP_115604.1
FAR1	XM_011520400.3	c.-7-124G>A		intron_variant			XP_011518702.1
FAR1	XM_047427690.1	c.-7-124G>A		intron_variant			XP_047283646.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FAR1	ENST00000354817.8	c.-7-124G>A		intron_variant		1	NM_032228.6	ENSP00000346874	P1
FAR1	ENST00000532701.1	c.-7-124G>A		intron_variant		2		ENSP00000437111

Frequencies

GnomAD3 genomes AF: 0.0322 AC: 4896 AN: 152122 Hom.: 113 Cov.: 32

Gnomad AFR AF: 0.00816

Gnomad AMI AF: 0.0307

Gnomad AMR AF: 0.0219

Gnomad ASJ AF: 0.0184

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00724

Gnomad FIN AF: 0.0786

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0469

Gnomad OTH AF: 0.0335

GnomAD4 exome AF: 0.0398 AC: 24590 AN: 618078 Hom.: 606 AF XY: 0.0386 AC XY: 12271 AN XY: 318076

Gnomad4 AFR exome AF: 0.00768

Gnomad4 AMR exome AF: 0.0242

Gnomad4 ASJ exome AF: 0.0189

Gnomad4 EAS exome AF: 0.0000950

Gnomad4 SAS exome AF: 0.00976

Gnomad4 FIN exome AF: 0.0665

Gnomad4 NFE exome AF: 0.0461

Gnomad4 OTH exome AF: 0.0372

GnomAD4 genome AF: 0.0322 AC: 4895 AN: 152240 Hom.: 113 Cov.: 32 AF XY: 0.0321 AC XY: 2387 AN XY: 74430

Gnomad4 AFR AF: 0.00813

Gnomad4 AMR AF: 0.0219

Gnomad4 ASJ AF: 0.0184

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00725

Gnomad4 FIN AF: 0.0786

Gnomad4 NFE AF: 0.0469

Gnomad4 OTH AF: 0.0331

Alfa AF: 0.0175 Hom.: 7

Bravo AF: 0.0279

Asia WGS AF: 0.00635 AC: 22 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 11, 2020	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	7.7
DANN	Benign	0.45

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: rs12282039; hg19: chr11-13716182;