17-50462421-C-G

Variant names:

• chr17-50462421-C-G
• rs754988573
• NM_025149.6:c.628C>G

Variant summary

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

The NM_025149.6(ACSF2):​c.628C>G​(p.Leu210Val) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 30)
• Consequence: ACSF2 NM_025149.6 missense, splice_region
• Scores: Splicing: ADA: 0.9708
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.75

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.325952).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACSF2	NM_025149.6	c.628C>G	p.Leu210Val	missense_variant, splice_region_variant	Exon 6 of 16	ENST00000300441.9	NP_079425.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACSF2	ENST00000300441.9	c.628C>G	p.Leu210Val	missense_variant, splice_region_variant	Exon 6 of 16	1	NM_025149.6	ENSP00000300441.4

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 39

GnomAD4 genome Cov.: 30

Bravo AF: 0.0000151

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 18, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.628C>G (p.L210V) alteration is located in exon 6 (coding exon 6) of the ACSF2 gene. This alteration results from a C to G substitution at nucleotide position 628, causing the leucine (L) at amino acid position 210 to be replaced by a valine (V). 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	0.12
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.34
CADD	Uncertain	25
DANN	Uncertain	1.0
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.21	T
M_CAP	Benign	0.079	D
MetaRNN	Benign	0.33	T
MetaSVM	Benign	-0.86	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.14
Sift	Pathogenic	0.0	D
MutPred		0.17		Loss of stability (P = 0.0063);
MVP		0.70
ClinPred		0.96	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.97
dbscSNV1_RF	Benign	0.65
SpliceAI score (max)		0.13		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: rs754988573; hg19: chr17-48539782;