15-50182707-G-A

Variant summary

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

The NM_003645.4(SLC27A2):c.280G>A(p.Ala94Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000155 in 1,613,882 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: SLC27A2 NM_003645.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.61

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

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=0.21679834).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC27A2	NM_003645.4	c.280G>A	p.Ala94Thr	missense_variant	1/10	ENST00000267842.10
SLC27A2	NM_001159629.2	c.280G>A	p.Ala94Thr	missense_variant	1/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC27A2	ENST00000267842.10	c.280G>A	p.Ala94Thr	missense_variant	1/10	1	NM_003645.4	P1
SLC27A2	ENST00000380902.8	c.280G>A	p.Ala94Thr	missense_variant	1/9	1
ATP8B4	ENST00000558829.1	c.-489C>T		5_prime_UTR_variant	1/4	3

Frequencies

GnomAD3 genomes AF: 0.0000328 AC: 5 AN: 152244 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000280 AC: 7 AN: 249942 Hom.: 0 AF XY: 0.0000370 AC XY: 5 AN XY: 135240

Gnomad AFR exome AF: 0.000124

Gnomad AMR exome AF: 0.0000579

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000177

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000137 AC: 20 AN: 1461520 Hom.: 0 Cov.: 35 AF XY: 0.0000138 AC XY: 10 AN XY: 727112

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000144

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000328 AC: 5 AN: 152362 Hom.: 0 Cov.: 33 AF XY: 0.0000403 AC XY: 3 AN XY: 74502

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.0000653

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000302

ExAC AF: 0.0000330 AC: 4

Asia WGS AF: 0.000289 AC: 1 AN: 3478

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 15, 2023

The c.280G>A (p.A94T) alteration is located in exon 1 (coding exon 1) of the SLC27A2 gene. This alteration results from a G to A substitution at nucleotide position 280, causing the alanine (A) at amino acid position 94 to be replaced by a threonine (T). 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	0.097
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.47
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Benign	0.21	T;.
Eigen	Benign	0.060
Eigen_PC	Benign	0.070
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.77	T;T
M_CAP	Benign	0.0094	T
MetaRNN	Benign	0.22	T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Uncertain	2.3	M;M
MutationTaster	Benign	0.98	D;D
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-2.0	N;N
REVEL	Benign	0.14
Sift	Benign	0.076	T;T
Sift4G	Benign	0.20	T;T
Polyphen		0.88	P;.
Vest4		0.13
MVP		0.45
MPC		1.0
ClinPred		0.15	T
GERP RS		1.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.10
gMVP		0.35

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: rs754950532; hg19: chr15-50474904;