10-95225320-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_207321.3(ACSM6):c.1231C>T(p.Pro411Ser) 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 benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: ACSM6 NM_207321.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.709

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3660568).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACSM6	NM_207321.3	c.1231C>T	p.Pro411Ser	missense_variant	10/11	ENST00000394005.4
LOC107984257	XR_007062253.1	n.347+228G>A		intron_variant, non_coding_transcript_variant
ACSM6	XM_047424638.1	c.1231C>T	p.Pro411Ser	missense_variant	10/10
ACSM6	XM_047424639.1	c.1231C>T	p.Pro411Ser	missense_variant	9/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACSM6	ENST00000394005.4	c.1231C>T	p.Pro411Ser	missense_variant	10/11	5	NM_207321.3	P1
ACSM6	ENST00000404473.6	c.*1054C>T		3_prime_UTR_variant, NMD_transcript_variant	10/10	1
ACSM6	ENST00000327739.7	c.*671C>T		3_prime_UTR_variant, NMD_transcript_variant	9/9	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

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

Apr 19, 2023

The c.1231C>T (p.P411S) alteration is located in exon 10 (coding exon 9) of the ACSM6 gene. This alteration results from a C to T substitution at nucleotide position 1231, causing the proline (P) at amino acid position 411 to be replaced by a serine (S). 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	0.14
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.53
Cadd	Benign	14
Dann	Uncertain	1.0
DEOGEN2	Benign	0.045	T;T
Eigen	Benign	0.022
Eigen_PC	Benign	-0.16
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.46	T;.
M_CAP	Benign	0.0028	T
MetaRNN	Benign	0.37	T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	1.8	L;L
MutationTaster	Benign	1.0	D;N;N
PROVEAN	Pathogenic	-5.6	D;D
REVEL	Benign	0.14
Sift	Benign	0.058	T;T
Sift4G	Benign	0.081	T;T
Polyphen		1.0	D;D
Vest4		0.12
MutPred		0.49		Loss of catalytic residue at P410 (P = 0.0109);Loss of catalytic residue at P410 (P = 0.0109);
MVP		0.38
MPC		0.035
ClinPred		0.90	D
GERP RS		1.4
Varity_R		0.17
gMVP		0.52

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr10-96985077;