10-95202016-G-C

Variant names:

• chr10-95202016-G-C
• rs921297291
• NM_207321.3:c.224G>C

Variant summary

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

The NM_207321.3(ACSM6):​c.224G>C​(p.Trp75Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000214 in 1,399,464 control chromosomes in the GnomAD database, with no homozygous occurrence. 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)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: ACSM6 NM_207321.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.50

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.886

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACSM6	NM_207321.3	c.224G>C	p.Trp75Ser	missense_variant	Exon 3 of 11	ENST00000394005.4	NP_997204.2
ACSM6	XM_047424638.1	c.224G>C	p.Trp75Ser	missense_variant	Exon 3 of 10		XP_047280594.1
ACSM6	XM_047424639.1	c.224G>C	p.Trp75Ser	missense_variant	Exon 2 of 9		XP_047280595.1
LOC107984257	XR_007062253.1	n.347+23532C>G		intron_variant	Intron 3 of 9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACSM6	ENST00000394005.4	c.224G>C	p.Trp75Ser	missense_variant	Exon 3 of 11	5	NM_207321.3	ENSP00000377573.3
ACSM6	ENST00000404473.6	n.*47G>C		non_coding_transcript_exon_variant	Exon 3 of 10	1		ENSP00000384922.2
ACSM6	ENST00000404473.6	n.*47G>C		3_prime_UTR_variant	Exon 3 of 10	1		ENSP00000384922.2
ACSM6	ENST00000327739.7	n.224G>C		non_coding_transcript_exon_variant	Exon 3 of 9	2		ENSP00000328491.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000191 AC: 3 AN: 156702 Hom.: 0 AF XY: 0.0000241 AC XY: 2 AN XY: 82968

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000122

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: 0.00000214 AC: 3 AN: 1399464 Hom.: 0 Cov.: 32 AF XY: 0.00000290 AC XY: 2 AN XY: 690238

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000840

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: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 09, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.224G>C (p.W75S) 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 224, causing the tryptophan (W) at amino acid position 75 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	Pathogenic	0.75
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	21
DANN	Benign	0.97
DEOGEN2	Benign	0.077	T;T
Eigen	Benign	0.049
Eigen_PC	Benign	-0.17
FATHMM_MKL	Benign	0.20	N
LIST_S2	Benign	0.37	T;.
M_CAP	Benign	0.0037	T
MetaRNN	Pathogenic	0.89	D;D
MetaSVM	Benign	-0.84	T
MutationAssessor	Uncertain	2.2	M;M
PROVEAN	Pathogenic	-13	D;D
REVEL	Benign	0.23
Sift	Pathogenic	0.0	D;D
Sift4G	Uncertain	0.0070	D;D
Polyphen		1.0	D;D
Vest4		0.65
MutPred		0.73		Gain of disorder (P = 2e-04);Gain of disorder (P = 2e-04);
MVP		0.45
MPC		0.034
ClinPred		0.96	D
GERP RS		1.3
Varity_R		0.69
gMVP		0.50

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs921297291; hg19: chr10-96961773;