Genetic Variant FADS6:p.Arg199Trp (chr17-74881253-G-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_178128.6(FADS6):c.595C>T(p.Arg199Trp) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000942 in 1,591,898 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000069 ( 0 hom. )

Consequence

FADS6
NM_178128.6 missense, splice_region

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.59

Variant links:

Genes affected

FADS6 (HGNC:30459): (fatty acid desaturase 6) Predicted to enable oxidoreductase activity, acting on paired donors, with oxidation of a pair of donors resulting in the reduction of molecular oxygen to two molecules of water. Predicted to be involved in lipid metabolic process. Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

FADS6 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.14681429).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FADS6	NM_178128.6 link	c.595C>T	p.Arg199Trp	missense_variant, splice_region_variant	Exon 4 of 6	ENST00000612771.5	NP_835229.3	Q8N9I5A0A087WYB9
FADS6	XM_005257224.6 link	c.595C>T	p.Arg199Trp	missense_variant, splice_region_variant	Exon 4 of 7		XP_005257281.2
FADS6	XM_017024458.3 link	c.541C>T	p.Arg181Trp	missense_variant, splice_region_variant	Exon 5 of 8		XP_016879947.1
FADS6	XM_047435759.1 link	c.136C>T	p.Arg46Trp	missense_variant, splice_region_variant	Exon 3 of 6		XP_047291715.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
FADS6	ENST00000612771.5 link	c.595C>T	p.Arg199Trp	missense_variant, splice_region_variant	Exon 4 of 6	1	NM_178128.6	ENSP00000481684.1	A0A087WYB9
FADS6	ENST00000579663.1 link	c.178C>T	p.Arg60Trp	missense_variant, splice_region_variant	Exon 2 of 3	3		ENSP00000464267.1	J3QRK6
FADS6	ENST00000413142.2 link	n.355+1277C>T		intron_variant	Intron 1 of 2	2

Frequencies

GnomAD3 genomes

AF:

0.0000328

AC:

AN:

152210

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000967

AC:

AN:

206858

AF XY:

0.00000892

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000671

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000695

AC:

AN:

1439570

Hom.:

Cov.:

AF XY:

0.00000560

AC XY:

AN XY:

714298

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33186

American (AMR)

AF:

0.00

AC:

AN:

40338

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25596

East Asian (EAS)

AF:

0.0000258

AC:

AN:

38772

South Asian (SAS)

AF:

0.0000600

AC:

AN:

83358

European-Finnish (FIN)

AF:

0.0000195

AC:

AN:

51222

Middle Eastern (MID)

AF:

0.000175

AC:

AN:

5706

European-Non Finnish (NFE)

AF:

0.00000182

AC:

AN:

1101780

Other (OTH)

AF:

0.00

AC:

AN:

59612

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.440

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000328

AC:

AN:

152328

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74488

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41588

American (AMR)

AF:

0.00

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5186

South Asian (SAS)

AF:

0.000414

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68026

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.565

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000120

AC:

ExAC

AF:

0.0000415

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 24, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.541C>T (p.R181W) alteration is located in exon 4 (coding exon 4) of the FADS6 gene. This alteration results from a C to T substitution at nucleotide position 541, causing the arginine (R) at amino acid position 181 to be replaced by a tryptophan (W). 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

-0.13

BayesDel_noAF

Benign

-0.42

CADD

Uncertain

(source)

DANN

Uncertain

1.0

Eigen

Uncertain

0.41

Eigen_PC

Uncertain

0.44

FATHMM_MKL

Uncertain

0.77

LIST_S2

Uncertain

0.88

D;D;D

M_CAP

Benign

0.013

MetaRNN

Benign

0.15

T;T;T

MetaSVM

Benign

-1.1

PhyloP100

1.6

PrimateAI

Benign

0.45

Sift4G

Benign

0.18

T;T;T

Vest4

0.36

MVP

0.28

ClinPred

0.62

GERP RS

5.1

Mutation Taster

=92/8

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Below is the list of publications found by LitVar for variant 17:74881253 G>A . It may be empty.

17-74881253-G-A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over