15-50182604-C-A

Variant names:

• chr15-50182604-C-A
• rs141946591
• NM_003645.4:c.177C>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_003645.4(SLC27A2):​c.177C>A​(p.Phe59Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000263 in 152,216 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency: Genomes: 𝑓 0.000026 (0 hom., cov: 33)
• Consequence: SLC27A2 NM_003645.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.606
• Publications: 2 publications found

Genes affected

SLC27A2 (HGNC:10996): (solute carrier family 27 member 2) The protein encoded by this gene is an isozyme of long-chain fatty-acid-coenzyme A ligase family. Although differing in substrate specificity, subcellular localization, and tissue distribution, all isozymes of this family convert free long-chain fatty acids into fatty acyl-CoA esters, and thereby play a key role in lipid biosynthesis and fatty acid degradation. This isozyme activates long-chain, branched-chain and very-long-chain fatty acids containing 22 or more carbons to their CoA derivatives. It is expressed primarily in liver and kidney, and is present in both endoplasmic reticulum and peroxisomes, but not in mitochondria. Its decreased peroxisomal enzyme activity is in part responsible for the biochemical pathology in X-linked adrenoleukodystrophy. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Apr 2009]

ATP8B4 (HGNC:13536): (ATPase phospholipid transporting 8B4 (putative)) This gene encodes a member of the cation transport ATPase (P-type) family and type IV subfamily. The encoded protein is involved in phospholipid transport in the cell membrane. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2013]

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.758

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003645.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC27A2	NM_003645.4	MANE Select	c.177C>A	p.Phe59Leu	missense	Exon 1 of 10	NP_003636.2	O14975-1
	SLC27A2	NM_001159629.2		c.177C>A	p.Phe59Leu	missense	Exon 1 of 9	NP_001153101.1	O14975-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC27A2	ENST00000267842.10	TSL:1 MANE Select	c.177C>A	p.Phe59Leu	missense	Exon 1 of 10	ENSP00000267842.5	O14975-1
	SLC27A2	ENST00000380902.8	TSL:1	c.177C>A	p.Phe59Leu	missense	Exon 1 of 9	ENSP00000370289.4	O14975-2
	SLC27A2	ENST00000895509.1		c.177C>A	p.Phe59Leu	missense	Exon 1 of 11	ENSP00000565568.1

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152216 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000811 AC: 2 AN: 246516 AF XY: 0.00000747

Gnomad AFR exome AF: 0.000126

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 36

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152216 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74366

African (AFR) AF: 0.0000965 AC: 4 AN: 41460

American (AMR) AF: 0.00 AC: 0 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68038

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000227

ESP6500AA AF: 0.000228 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000165 AC: 2

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	18
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.64	D
Eigen	Benign	-0.66
Eigen_PC	Benign	-0.85
FATHMM_MKL	Benign	0.42	N
LIST_S2	Benign	0.79	T
M_CAP	Benign	0.059	D
MetaRNN	Pathogenic	0.76	D
MetaSVM	Benign	-0.97	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		-0.61
PrimateAI	Pathogenic	0.80	T
PROVEAN	Pathogenic	-5.2	D
REVEL	Benign	0.20
Sift	Benign	0.072	T
Sift4G	Benign	0.11	T
Polyphen		0.85	P
Vest4		0.74
MutPred		0.57		Gain of disorder (P = 0.1226)
MVP		0.36
MPC		1.9
ClinPred		0.97	D
GERP RS		-1.1
PromoterAI		-0.0099	Neutral
Varity_R		0.45
gMVP		0.66

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

Other links and lift over

dbSNP: rs141946591; hg19: chr15-50474801;