16-20781756-T-C

Position:

• chr16-20781756-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_005622.4(ACSM3):​c.988T>C​(p.Tyr330His) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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)
• Consequence: ACSM3 NM_005622.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.95

Genes affected

ACSM3 (HGNC:10522): (acyl-CoA synthetase medium chain family member 3) Enables butyrate-CoA ligase activity. Predicted to be involved in acyl-CoA metabolic process and fatty acid biosynthetic process. Located in mitochondrion. Implicated in IgA glomerulonephritis. Biomarker of ulcerative colitis. [provided by Alliance of Genome Resources, Apr 2022]

ERI2 (HGNC:30541): (ERI1 exoribonuclease family member 2) Predicted to enable 3'-5'-exoribonuclease activity. Predicted to be involved in exonucleolytic trimming to generate mature 3'-end of 5.8S rRNA from tricistronic rRNA transcript (SSU-rRNA, 5.8S rRNA, LSU-rRNA). [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.918

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ACSM3	NM_005622.4	c.988T>C	p.Tyr330His	missense_variant	7/14	ENST00000289416.10	NP_005613.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ACSM3	ENST00000289416.10	c.988T>C	p.Tyr330His	missense_variant	7/14	1	NM_005622.4	ENSP00000289416	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

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

Sep 01, 2021

The c.988T>C (p.Y330H) alteration is located in exon 7 (coding exon 6) of the ACSM3 gene. This alteration results from a T to C substitution at nucleotide position 988, causing the tyrosine (Y) at amino acid position 330 to be replaced by a histidine (H). 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	0.79
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.070
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.31	T;.
Eigen	Pathogenic	0.72
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.91	D;D
M_CAP	Benign	0.035	D
MetaRNN	Pathogenic	0.92	D;D
MetaSVM	Uncertain	-0.26	T
MutationAssessor	Pathogenic	4.0	H;H
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.60	T
PROVEAN	Pathogenic	-4.5	D;D
REVEL	Uncertain	0.55
Sift	Uncertain	0.023	D;D
Sift4G	Uncertain	0.030	D;D
Polyphen		1.0	D;D
Vest4		0.82
MutPred		0.78		Gain of catalytic residue at M332 (P = 0.1715);Gain of catalytic residue at M332 (P = 0.1715);
MVP		0.70
MPC		0.58
ClinPred		1.0	D
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.64
gMVP		0.76

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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

Other links and lift over

dbSNP: rs2080358039; hg19: chr16-20793078;