17-50460821-G-T

Variant names:

• chr17-50460821-G-T
• rs754538592
• NM_025149.6:c.273G>T

Variant summary

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

The NM_001288972.2(ACSF2):​c.-125G>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,852 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: ACSF2 NM_001288972.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.13

Genes affected

ACSF2 (HGNC:26101): (acyl-CoA synthetase family member 2) Enables medium-chain fatty acid-CoA ligase activity. Predicted to be involved in fatty acid metabolic process. Predicted to be located in mitochondrial matrix. [provided by Alliance of Genome Resources, Apr 2022]

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=0.23787561).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACSF2	NM_025149.6	c.273G>T	p.Leu91Phe	missense_variant	Exon 2 of 16	ENST00000300441.9	NP_079425.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACSF2	ENST00000300441.9	c.273G>T	p.Leu91Phe	missense_variant	Exon 2 of 16	1	NM_025149.6	ENSP00000300441.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000122 AC: 3 AN: 246858 Hom.: 0 AF XY: 0.0000150 AC XY: 2 AN XY: 133512

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000164

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459852 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726050

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 13, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.273G>T (p.L91F) alteration is located in exon 2 (coding exon 2) of the ACSF2 gene. This alteration results from a G to T substitution at nucleotide position 273, causing the leucine (L) at amino acid position 91 to be replaced by a phenylalanine (F). 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	0.23
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Benign	0.31	T;.;T;.;.
Eigen	Benign	-0.044
Eigen_PC	Benign	0.057
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.82	T;T;T;T;T
M_CAP	Benign	0.028	D
MetaRNN	Benign	0.24	T;T;T;T;T
MetaSVM	Benign	-0.85	T
MutationAssessor	Uncertain	2.5	M;.;.;.;M
PrimateAI	Benign	0.39	T
PROVEAN	Uncertain	-2.7	D;D;D;D;D
REVEL	Benign	0.15
Sift	Uncertain	0.020	D;D;D;D;D
Sift4G	Uncertain	0.022	D;D;D;D;D
Polyphen		0.032	B;.;B;.;.
Vest4		0.14
MutPred		0.45		Gain of catalytic residue at L91 (P = 0.0412);Gain of catalytic residue at L91 (P = 0.0412);Gain of catalytic residue at L91 (P = 0.0412);.;Gain of catalytic residue at L91 (P = 0.0412);
MVP		0.69
MPC		0.61
ClinPred		0.59	D
GERP RS		3.5
Varity_R		0.20
gMVP		0.71

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: rs754538592; hg19: chr17-48538182;