12-7317264-T-C

Position:

• chr12-7317264-T-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Moderate BP6_Moderate

The NM_001080454.2(ACSM4):​c.748T>C​(p.Phe250Leu) variant causes a missense 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. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: ACSM4 NM_001080454.2 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.05

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.071074426).
• BP6: Variant 12-7317264-T-C is Benign according to our data. Variant chr12-7317264-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 3140643.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ACSM4	NM_001080454.2	c.748T>C	p.Phe250Leu	missense_variant	4/13	ENST00000399422.5	NP_001073923.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ACSM4	ENST00000399422.5	c.748T>C	p.Phe250Leu	missense_variant	4/13	5	NM_001080454.2	ENSP00000382349	P1
ACSM4	ENST00000533292.1	n.202T>C		non_coding_transcript_exon_variant	2/3	3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 04, 2024

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.59
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	6.9
DANN	Benign	0.39
DEOGEN2	Benign	0.0055	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.031	T
M_CAP	Benign	0.0021	T
MetaRNN	Benign	0.071	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.12	N
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-0.060	N
REVEL	Benign	0.037
Sift	Benign	0.84	T
Sift4G	Benign	0.69	T
Polyphen		0.0	B
Vest4		0.24
MutPred		0.59		Gain of catalytic residue at L252 (P = 0.0026);
MVP		0.067
MPC		0.087
ClinPred		0.044	T
GERP RS		2.6
Varity_R		0.060
gMVP		0.31

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: chr12-7469860;