Genetic Variant NM_025149.6:c.628C>T (chr17-50462421-C-T) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_025149.6(ACSF2):c.628C>T(p.Leu210Phe) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,262 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L210V) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 30)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

ACSF2
NM_025149.6 missense, splice_region

Scores

Splicing: ADA: 0.9737

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.75

Publications

0 publications found

Variant links:

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]

ACSF2 links:

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ACMG classification

Classification was made for transcript

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

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ACSF2	NM_025149.6	MANE Select	c.628C>T	p.Leu210Phe	missense splice_region	Exon 6 of 16	NP_079425.3
ACSF2	NM_001288968.2		c.703C>T	p.Leu235Phe	missense splice_region	Exon 7 of 17	NP_001275897.1	Q96CM8-2
ACSF2	NM_001288969.2		c.589C>T	p.Leu197Phe	missense splice_region	Exon 6 of 16	NP_001275898.1	Q96CM8-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ACSF2	ENST00000300441.9	TSL:1 MANE Select	c.628C>T	p.Leu210Phe	missense splice_region	Exon 6 of 16	ENSP00000300441.4	Q96CM8-1
ACSF2	ENST00000893269.1		c.577C>T	p.Leu193Phe	missense	Exon 6 of 16	ENSP00000563328.1
ACSF2	ENST00000427954.6	TSL:2	c.703C>T	p.Leu235Phe	missense splice_region	Exon 7 of 17	ENSP00000401831.2	Q96CM8-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461262

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726878

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44712

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26116

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.00

AC:

AN:

86234

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53030

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111844

Other (OTH)

AF:

0.0000166

AC:

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Benign

-0.21

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

Eigen

Uncertain

0.59

Eigen_PC

Uncertain

0.58

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Benign

0.26

M_CAP

Uncertain

0.11

MetaRNN

Benign

0.30

MetaSVM

Benign

-0.65

PhyloP100

2.7

PROVEAN

Benign

0.15

REVEL

Benign

0.15

Sift

Pathogenic

0.0

MutPred

0.078

Loss of glycosylation at P183 (P = 0.0565)

MVP

0.67

ClinPred

0.99

GERP RS

5.6

Varity_R

0.39

Mutation Taster

=29/71

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

0.97

dbscSNV1_RF

Pathogenic

0.79

SpliceAI score (max)

0.12

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over