16-20542945-A-T

Position:

• chr16-20542945-A-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001105069.2(ACSM2B):​c.1478T>A​(p.Val493Glu) variant causes a missense change. The variant allele was found at a frequency of 0.00000547 in 1,461,594 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: ACSM2B NM_001105069.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.42

Genes affected

ACSM2B (HGNC:30931): (acyl-CoA synthetase medium chain family member 2B) Enables benzoate-CoA ligase activity. Predicted to be involved in acyl-CoA metabolic process and fatty acid biosynthetic process. Located in mitochondrion. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.982

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACSM2B	NM_001105069.2	c.1478T>A	p.Val493Glu	missense_variant	12/14	ENST00000329697.10
ACSM2B	NM_182617.4	c.1478T>A	p.Val493Glu	missense_variant	13/15
ACSM2B	NM_001410902.1	c.1241T>A	p.Val414Glu	missense_variant	11/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACSM2B	ENST00000329697.10	c.1478T>A	p.Val493Glu	missense_variant	12/14	1	NM_001105069.2	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000547 AC: 8 AN: 1461594 Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4 AN XY: 727112

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: 0.0000928

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 07, 2022

The c.1478T>A (p.V493E) alteration is located in exon 13 (coding exon 11) of the ACSM2B gene. This alteration results from a T to A substitution at nucleotide position 1478, causing the valine (V) at amino acid position 493 to be replaced by a glutamic acid (E). 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	Pathogenic	0.91
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.26
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.17	T;T;.;T;T
Eigen	Uncertain	0.36
Eigen_PC	Benign	0.12
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Pathogenic	0.99	.;D;D;.;.
M_CAP	Benign	0.020	T
MetaRNN	Pathogenic	0.98	D;D;D;D;D
MetaSVM	Uncertain	0.34	D
MutationAssessor	Pathogenic	4.1	H;H;.;H;H
MutationTaster	Benign	0.99	D;D;D;D
PrimateAI	Uncertain	0.52	T
PROVEAN	Pathogenic	-5.3	D;.;D;D;D
REVEL	Pathogenic	0.69
Sift	Pathogenic	0.0	D;.;D;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D;D
Polyphen		1.0	D;D;.;D;D
Vest4		0.79
MutPred		0.89		Gain of disorder (P = 0.0049);Gain of disorder (P = 0.0049);.;Gain of disorder (P = 0.0049);Gain of disorder (P = 0.0049);
MVP		0.79
MPC		1.0
ClinPred		0.97	D
GERP RS		3.1
Varity_R		0.81
gMVP		0.88

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: chr16-20554267;