11-61812491-C-A

Position:

• chr11-61812491-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_013402.7(FADS1):​c.664G>T​(p.Val222Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/18 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)
• Consequence: FADS1 NM_013402.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0920

Genes affected

FADS1 (HGNC:3574): (fatty acid desaturase 1) The protein encoded by this gene is a member of the fatty acid desaturase (FADS) gene family. Desaturase enzymes regulate unsaturation of fatty acids through the introduction of double bonds between defined carbons of the fatty acyl chain. FADS family members are considered fusion products composed of an N-terminal cytochrome b5-like domain and a C-terminal multiple membrane-spanning desaturase portion, both of which are characterized by conserved histidine motifs. This gene is clustered with family members FADS1 and FADS2 at 11q12-q13.1; this cluster is thought to have arisen evolutionarily from gene duplication based on its similar exon/intron organization. [provided by RefSeq, Jul 2008]

FADS2 (HGNC:3575): (fatty acid desaturase 2) The protein encoded by this gene is a member of the fatty acid desaturase (FADS) gene family. Desaturase enzymes regulate unsaturation of fatty acids through the introduction of double bonds between defined carbons of the fatty acyl chain. FADS family members are considered fusion products composed of an N-terminal cytochrome b5-like domain and a C-terminal multiple membrane-spanning desaturase portion, both of which are characterized by conserved histidine motifs. This gene is clustered with family members at 11q12-q13.1; this cluster is thought to have arisen evolutionarily from gene duplication based on its similar exon/intron organization. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jul 2013]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07214576).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FADS1	NM_013402.7	c.664G>T	p.Val222Leu	missense_variant	3/12	ENST00000350997.12	NP_037534.5
FADS1	XM_011545022.3	c.451G>T	p.Val151Leu	missense_variant	3/12		XP_011543324.1
FADS1	XM_047426935.1	c.241G>T	p.Val81Leu	missense_variant	3/12		XP_047282891.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FADS1	ENST00000350997.12	c.664G>T	p.Val222Leu	missense_variant	3/12	1	NM_013402.7	ENSP00000322229	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000660 Hom.: 0

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

Aug 02, 2021

The c.664G>T (p.V222L) alteration is located in exon 3 (coding exon 3) of the FADS1 gene. This alteration results from a G to T substitution at nucleotide position 664, causing the valine (V) at amino acid position 222 to be replaced by a leucine (L). 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
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	14
DANN	Benign	0.64
DEOGEN2	Benign	0.0090	.;.;.;.;T;.;.;T;T;T;.
Eigen	Benign	-0.69
Eigen_PC	Benign	-0.54
FATHMM_MKL	Benign	0.36	N
LIST_S2	Benign	0.76	T;.;T;T;T;T;T;T;T;T;T
M_CAP	Benign	0.0093	T
MetaRNN	Benign	0.072	T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	0.98	N;N;N;D
PrimateAI	Benign	0.44	T
PROVEAN	Benign	0.010	N;N;N;N;N;N;N;N;N;N;N
REVEL	Benign	0.12
Sift	Benign	0.74	T;T;T;T;T;T;T;T;T;T;T
Sift4G	Benign	0.63	T;T;T;T;T;T;T;.;.;T;.
Vest4		0.20
MVP		0.055
MPC		1.3
ClinPred		0.063	T
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
gMVP		0.69

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: rs1425572629; hg19: chr11-61579963;