Variant 16-20545257-A-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_001105069.2(ACSM2B):c.1181T>A(p.Val394Asp) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000000685 in 1,460,562 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

ACSM2B
NM_001105069.2 missense, splice_region

Scores

Splicing: ADA: 0.004088

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.57

Variant links:

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]

ACSM2B links:

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ACMG classification

Classification made for transcript

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, 0.966

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
ACSM2B	NM_001105069.2 linkuse as main transcript	c.1181T>A	p.Val394Asp	missense_variant, splice_region_variant	10/14	ENST00000329697.10
ACSM2B	NM_182617.4 linkuse as main transcript	c.1181T>A	p.Val394Asp	missense_variant, splice_region_variant	11/15
ACSM2B	NM_001410902.1 linkuse as main transcript	c.944T>A	p.Val315Asp	missense_variant, splice_region_variant	9/13
ACSM2B	XR_001751899.3 linkuse as main transcript	n.1350T>A		splice_region_variant, non_coding_transcript_exon_variant	10/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACSM2B	ENST00000329697.10 linkuse as main transcript	c.1181T>A	p.Val394Asp	missense_variant, splice_region_variant	10/14	1	NM_001105069.2	P1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1460562

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726492

show subpopulations

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:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 26, 2022

The c.1181T>A (p.V394D) alteration is located in exon 11 (coding exon 9) of the ACSM2B gene. This alteration results from a T to A substitution at nucleotide position 1181, causing the valine (V) at amino acid position 394 to be replaced by an aspartic acid (D). 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

0.93

BayesDel_addAF

Pathogenic

0.26

BayesDel_noAF

Uncertain

0.13

Cadd

Uncertain

Dann

Uncertain

0.98

DEOGEN2

Benign

0.15

T;T;.;T;T;.

Eigen

Benign

0.13

Eigen_PC

Benign

-0.016

FATHMM_MKL

Uncertain

0.86

M_CAP

Benign

0.015

MetaRNN

Pathogenic

0.97

D;D;D;D;D;D

MetaSVM

Benign

-0.44

MutationAssessor

Pathogenic

3.2

M;M;.;M;M;.

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Benign

0.39

PROVEAN

Pathogenic

-5.8

D;.;D;D;D;.

REVEL

Uncertain

0.41

Sift

Pathogenic

0.0

D;.;D;D;D;.

Sift4G

Pathogenic

0.0010

D;D;D;D;D;D

Polyphen

0.58

P;P;.;P;P;.

Vest4

0.89

MutPred

0.87

Gain of disorder (P = 0.0307);Gain of disorder (P = 0.0307);.;Gain of disorder (P = 0.0307);Gain of disorder (P = 0.0307);.;

MVP

0.59

MPC

0.72

ClinPred

0.99

GERP RS

3.4

Varity_R

0.96

gMVP

0.87

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0041

dbscSNV1_RF

Benign

0.074

SpliceAI score (max)

0.050

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over