chr17-50462421-C-G

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 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. 13/20 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
• Publications: 1 publications found

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

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_025149.6. 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
	ACSF2	NM_025149.6	MANE Select	c.628C>G	p.Leu210Val	missense splice_region	Exon 6 of 16	NP_079425.3
	ACSF2	NM_001288968.2		c.703C>G	p.Leu235Val	missense splice_region	Exon 7 of 17	NP_001275897.1	Q96CM8-2
	ACSF2	NM_001288969.2		c.589C>G	p.Leu197Val	missense splice_region	Exon 6 of 16	NP_001275898.1	Q96CM8-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACSF2	ENST00000300441.9	TSL:1 MANE Select	c.628C>G	p.Leu210Val	missense splice_region	Exon 6 of 16	ENSP00000300441.4	Q96CM8-1
	ACSF2	ENST00000893269.1		c.577C>G	p.Leu193Val	missense	Exon 6 of 16	ENSP00000563328.1
	ACSF2	ENST00000427954.6	TSL:2	c.703C>G	p.Leu235Val	missense splice_region	Exon 7 of 17	ENSP00000401831.2	Q96CM8-2

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 39

GnomAD4 genome Cov.: 30

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000151

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		2.7
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
Varity_R		0.29

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

Other links and lift over

dbSNP: rs754988573; hg19: chr17-48539782;