12-29293316-A-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001271783.2(FAR2):c.206A>G(p.Lys69Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000014 in 1,429,452 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: FAR2 NM_001271783.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.27

Genes affected

FAR2 (HGNC:25531): (fatty acyl-CoA reductase 2) This gene belongs to the short chain dehydrogenase/reductase superfamily. It encodes a reductase enzyme involved in the first step of wax biosynthesis wherein fatty acids are converted to fatty alcohols. The encoded peroxisomal protein utilizes saturated fatty acids of 16 or 18 carbons as preferred substrates. Alternatively spliced transcript variants have been observed for this gene. Related pseudogenes have been identified on chromosomes 2, 14 and 22. [provided by RefSeq, Nov 2012]

(HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.04588443).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FAR2	NM_001271783.2	c.206A>G	p.Lys69Arg	missense_variant	3/12	ENST00000536681.8
LOC100506606	NR_103860.1	n.694T>C		non_coding_transcript_exon_variant	4/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FAR2	ENST00000536681.8	c.206A>G	p.Lys69Arg	missense_variant	3/12	1	NM_001271783.2	P1
	ENST00000553105.1	n.694T>C		non_coding_transcript_exon_variant	4/7	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000140 AC: 2 AN: 1429452 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 710158

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000182

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 10, 2022

The c.206A>G (p.K69R) alteration is located in exon 3 (coding exon 2) of the FAR2 gene. This alteration results from a A to G substitution at nucleotide position 206, causing the lysine (K) at amino acid position 69 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.71
Cadd	Benign	16
Dann	Benign	0.88
DEOGEN2	Benign	0.040	T;T
Eigen	Benign	-0.69
Eigen_PC	Benign	-0.43
FATHMM_MKL	Benign	0.50	D
M_CAP	Benign	0.0022	T
MetaRNN	Benign	0.046	T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	-0.67	N;N
MutationTaster	Benign	1.0	D;N;N
PrimateAI	Benign	0.46	T
PROVEAN	Benign	2.3	N;N
REVEL	Benign	0.096
Sift	Benign	1.0	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.0	B;B
Vest4		0.066
MutPred		0.52		Gain of catalytic residue at F65 (P = 0.0203);Gain of catalytic residue at F65 (P = 0.0203);
MVP		0.16
MPC		0.37
ClinPred		0.88	D
GERP RS		3.1
Varity_R		0.054
gMVP		0.23

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: rs1348703872; hg19: chr12-29446249;