12-7317259-T-C

Variant names:

• chr12-7317259-T-C
• NM_001080454.2:c.743T>C

Variant summary

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

The NM_001080454.2(ACSM4):​c.743T>C​(p.Ile248Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000000699 in 1,431,388 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: ACSM4 NM_001080454.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.20

Genes affected

ACSM4 (HGNC:32016): (acyl-CoA synthetase medium chain family member 4) Predicted to enable decanoate-CoA ligase activity and fatty-acyl-CoA synthase activity. Predicted to be involved in acyl-CoA metabolic process and fatty acid biosynthetic process. Predicted to be active in mitochondrial matrix. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACSM4	NM_001080454.2	c.743T>C	p.Ile248Thr	missense_variant	Exon 4 of 13	ENST00000399422.5	NP_001073923.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACSM4	ENST00000399422.5	c.743T>C	p.Ile248Thr	missense_variant	Exon 4 of 13	5	NM_001080454.2	ENSP00000382349.4
ACSM4	ENST00000533292.1	n.197T>C		non_coding_transcript_exon_variant	Exon 2 of 3	3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.99e-7 AC: 1 AN: 1431388 Hom.: 0 Cov.: 30 AF XY: 0.00000141 AC XY: 1 AN XY: 708982

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000122

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 01, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.743T>C (p.I248T) alteration is located in exon 4 (coding exon 4) of the ACSM4 gene. This alteration results from a T to C substitution at nucleotide position 743, causing the isoleucine (I) at amino acid position 248 to be replaced by a threonine (T). 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	0.20
BayesDel_addAF	Benign	-0.052	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.13	T
Eigen	Benign	-0.087
Eigen_PC	Benign	-0.027
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.40	T
M_CAP	Benign	0.0089	T
MetaRNN	Uncertain	0.70	D
MetaSVM	Benign	-0.91	T
MutationAssessor	Uncertain	2.8	M
PrimateAI	Uncertain	0.65	T
PROVEAN	Uncertain	-3.1	D
REVEL	Benign	0.20
Sift	Uncertain	0.017	D
Sift4G	Benign	0.094	T
Polyphen		0.42	B
Vest4		0.71
MutPred		0.60		Gain of catalytic residue at I248 (P = 0);
MVP		0.38
MPC		0.13
ClinPred		0.90	D
GERP RS		3.7
Varity_R		0.19
gMVP		0.25

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-7469855;