10-95202009-G-C

Variant summary

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

The NM_207321.3(ACSM6):c.217G>C(p.Ala73Pro) 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 pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ACSM6 NM_207321.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.98

Genes affected

ACSM6 (HGNC:31665): (acyl-CoA synthetase medium chain family member 6) 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]

LOC107984257 (HGNC:):

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, 0.972

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACSM6	NM_207321.3	c.217G>C	p.Ala73Pro	missense_variant	3/11	ENST00000394005.4
LOC107984257	XR_007062253.1	n.347+23539C>G		intron_variant, non_coding_transcript_variant
ACSM6	XM_047424638.1	c.217G>C	p.Ala73Pro	missense_variant	3/10
ACSM6	XM_047424639.1	c.217G>C	p.Ala73Pro	missense_variant	2/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACSM6	ENST00000394005.4	c.217G>C	p.Ala73Pro	missense_variant	3/11	5	NM_207321.3	P1
ACSM6	ENST00000404473.6	c.*40G>C		3_prime_UTR_variant, NMD_transcript_variant	3/10	1
ACSM6	ENST00000327739.7	c.217G>C	p.Ala73Pro	missense_variant, NMD_transcript_variant	3/9	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

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

Jul 27, 2022

The c.217G>C (p.A73P) alteration is located in exon 3 (coding exon 2) of the ACSM6 gene. This alteration results from a G to C substitution at nucleotide position 217, causing the alanine (A) at amino acid position 73 to be replaced by a proline (P). 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	0.57
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.030
Cadd	Benign	19
Dann	Uncertain	0.99
DEOGEN2	Benign	0.29	T;T
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.46
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.48	T;.
M_CAP	Benign	0.0034	T
MetaRNN	Pathogenic	0.97	D;D
MetaSVM	Benign	-0.83	T
MutationAssessor	Pathogenic	3.0	M;M
MutationTaster	Benign	1.0	N;N;N
PROVEAN	Pathogenic	-4.6	D;D
REVEL	Uncertain	0.39
Sift	Uncertain	0.0020	D;D
Sift4G	Uncertain	0.012	D;D
Polyphen		1.0	D;D
Vest4		0.70
MutPred		0.88		Gain of catalytic residue at P72 (P = 0.0119);Gain of catalytic residue at P72 (P = 0.0119);
MVP		0.48
MPC		0.20
ClinPred		0.95	D
GERP RS		0.38
Varity_R		0.56
gMVP		0.72

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: chr10-96961766;