10-112376345-C-G

Variant names:

• chr10-112376345-C-G
• rs754412834
• ENST00000356116.6:c.36C>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_016234.4(ACSL5):​c.36C>G​(p.Asn12Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,890 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ACSL5 NM_016234.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.618
• Publications: 0 publications found

Genes affected

ACSL5 (HGNC:16526): (acyl-CoA synthetase long chain family member 5) The protein encoded by this gene is an isozyme of the 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 is highly expressed in uterus and spleen, and in trace amounts in normal brain, but has markedly increased levels in malignant gliomas. This gene functions in mediating fatty acid-induced glioma cell growth. Three transcript variants encoding two different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

ACSL5 Gene-Disease associations (from GenCC):

• diarrhea 13

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.05885464).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016234.4. 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
	ACSL5	NM_203379.2	MANE Select	c.-30+2076C>G		intron	N/A	NP_976313.1	Q9ULC5-1
	ACSL5	NM_016234.4		c.36C>G	p.Asn12Lys	missense	Exon 1 of 21	NP_057318.2
	ACSL5	NM_001387037.1		c.36C>G	p.Asn12Lys	missense	Exon 1 of 20	NP_001373966.1	A0A8C8L3F5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACSL5	ENST00000356116.6	TSL:1	c.36C>G	p.Asn12Lys	missense	Exon 1 of 21	ENSP00000348429.1	Q9ULC5-3
	ACSL5	ENST00000354273.5	TSL:1	c.36C>G	p.Asn12Lys	missense	Exon 1 of 19	ENSP00000346223.5	A0A8C8KCK5
	ACSL5	ENST00000354655.9	TSL:2 MANE Select	c.-30+2076C>G		intron	N/A	ENSP00000346680.4	Q9ULC5-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461890 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727246

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1112010

Other (OTH) AF: 0.00 AC: 0 AN: 60396

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	11
DANN	Uncertain	0.99
Eigen	Benign	-0.78
Eigen_PC	Benign	-0.83
FATHMM_MKL	Benign	0.023	N
LIST_S2	Benign	0.31	T
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.059	T
MetaSVM	Benign	-1.0	T
PhyloP100		0.62
PrimateAI	Benign	0.32	T
PROVEAN	Benign	0.030	N
REVEL	Benign	0.10
Sift	Uncertain	0.013	D
Sift4G	Benign	0.15	T
Polyphen		0.0010	B
Vest4		0.17
MutPred		0.089		Gain of methylation at N12 (P = 0.0127)
MVP		0.12
MPC		0.46
ClinPred		0.97	D
GERP RS		1.6
PromoterAI		0.0034	Neutral
gMVP		0.079
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs754412834; hg19: chr10-114136103;