Variant 16-20427789-C-T details in Genebe, Genetics Data Aggregator

Variant summary

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

The NM_017888.3(ACSM5):c.923C>T(p.Thr308Ile) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000186 in 1,611,578 control chromosomes in the GnomAD database, with no homozygous occurrence. 13/23 in silico tools predict a benign 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: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000020 ( 0 hom. )

Consequence

ACSM5
NM_017888.3 missense, splice_region

Scores

Splicing: ADA: 0.00008973

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.21

Variant links:

Genes affected

ACSM5 (HGNC:26060): (acyl-CoA synthetase medium chain family member 5) Predicted to enable fatty acid 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]

ACSM5 links:

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ACMG classification

Classification made for transcript

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/exons	MANE	Protein
ACSM5	NM_017888.3 linkuse as main transcript	c.923C>T	p.Thr308Ile	missense_variant, splice_region_variant	7/14	ENST00000331849.8	NP_060358.2
ACSM5	NM_001324372.2 linkuse as main transcript	c.923C>T	p.Thr308Ile	missense_variant, splice_region_variant	7/14		NP_001311301.1
ACSM5	NM_001324371.2 linkuse as main transcript	c.923C>T	p.Thr308Ile	missense_variant, splice_region_variant	7/14		NP_001311300.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ACSM5	ENST00000331849.8 linkuse as main transcript	c.923C>T	p.Thr308Ile	missense_variant, splice_region_variant	7/14	1	NM_017888.3	ENSP00000327916	P1	Q6NUN0-1
ACSM5	ENST00000570305.5 linkuse as main transcript	n.502C>T		splice_region_variant, non_coding_transcript_exon_variant	3/5	3
ACSM5	ENST00000574748.5 linkuse as main transcript	n.227C>T		splice_region_variant, non_coding_transcript_exon_variant	2/4	3
ACSM5	ENST00000573920.1 linkuse as main transcript	c.283-1889C>T		intron_variant, NMD_transcript_variant		3		ENSP00000461752

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152188

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000398

AC:

AN:

251344

Hom.:

AF XY:

0.0000368

AC XY:

AN XY:

135850

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000199

AC:

AN:

1459390

Hom.:

Cov.:

AF XY:

0.0000165

AC XY:

AN XY:

726186

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000268

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000126

Gnomad4 OTH exome

AF:

0.0000332

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152188

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74330

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000491

ExAC

AF:

0.00000824

AC:

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

Jan 06, 2023

The c.923C>T (p.T308I) alteration is located in exon 7 (coding exon 6) of the ACSM5 gene. This alteration results from a C to T substitution at nucleotide position 923, causing the threonine (T) at amino acid position 308 to be replaced by an isoleucine (I). 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

0.12

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.46

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.033

Eigen

Benign

0.088

Eigen_PC

Benign

0.018

FATHMM_MKL

Benign

0.74

LIST_S2

Uncertain

0.92

M_CAP

Benign

0.012

MetaRNN

Uncertain

0.50

MetaSVM

Benign

-0.94

MutationAssessor

Benign

1.6

MutationTaster

Benign

0.93

PrimateAI

Uncertain

0.58

PROVEAN

Pathogenic

-4.5

REVEL

Benign

0.19

Sift

Benign

0.12

Sift4G

Benign

0.47

Polyphen

1.0

Vest4

0.48

MutPred

0.58

Gain of ubiquitination at K311 (P = 0.0462);

MVP

0.69

MPC

0.32

ClinPred

0.57

GERP RS

3.0

Varity_R

0.25

gMVP

0.58

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000090

dbscSNV1_RF

Benign

0.0

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over