17-74881225-G-T

Variant names:

• chr17-74881225-G-T
• rs1389296145
• NM_178128.6:c.623C>A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_178128.6(FADS6):​c.623C>A​(p.Ala208Asp) variant causes a missense change. The variant allele was found at a frequency of 0.000000689 in 1,451,614 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: FADS6 NM_178128.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.07

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.35939306).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FADS6	NM_178128.6	c.623C>A	p.Ala208Asp	missense_variant	Exon 4 of 6	ENST00000612771.5	NP_835229.3
FADS6	XM_005257224.6	c.623C>A	p.Ala208Asp	missense_variant	Exon 4 of 7		XP_005257281.2
FADS6	XM_017024458.3	c.569C>A	p.Ala190Asp	missense_variant	Exon 5 of 8		XP_016879947.1
FADS6	XM_047435759.1	c.164C>A	p.Ala55Asp	missense_variant	Exon 3 of 6		XP_047291715.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FADS6	ENST00000612771.5	c.623C>A	p.Ala208Asp	missense_variant	Exon 4 of 6	1	NM_178128.6	ENSP00000481684.1
FADS6	ENST00000579663.1	c.206C>A	p.Ala69Asp	missense_variant	Exon 2 of 3	3		ENSP00000464267.1
FADS6	ENST00000413142.2	n.355+1305C>A		intron_variant	Intron 1 of 2	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.89e-7 AC: 1 AN: 1451614 Hom.: 0 Cov.: 31 AF XY: 0.00000139 AC XY: 1 AN XY: 721378

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: 9.03e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 03, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.569C>A (p.A190D) alteration is located in exon 4 (coding exon 4) of the FADS6 gene. This alteration results from a C to A substitution at nucleotide position 569, causing the alanine (A) at amino acid position 190 to be replaced by an aspartic acid (D). 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	-0.12	T
BayesDel_noAF	Benign	-0.41
CADD	Uncertain	24
DANN	Uncertain	1.0
Eigen	Benign	0.13
Eigen_PC	Benign	0.084
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.74	T;T;T
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.36	T;T;T
MetaSVM	Benign	-1.1	T
PrimateAI	Uncertain	0.57	T
Sift4G	Uncertain	0.019	D;D;D
Vest4		0.83
MVP		0.23
ClinPred		0.93	D
GERP RS		3.9

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: rs1389296145; hg19: chr17-72877355;