7-87349159-T-A

Position:

• chr7-87349159-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_021151.4(CROT):​c.91T>A​(p.Ser31Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000697 in 1,433,904 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: CROT NM_021151.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.07

Genes affected

CROT (HGNC:2366): (carnitine O-octanoyltransferase) This gene encodes a member of the carnitine/choline acetyltransferase family. The encoded protein converts 4,8-dimethylnonanoyl-CoA to its corresponding carnitine ester. This transesterification occurs in the peroxisome and is necessary for transport of medium- and long- chain acyl-CoA molecules out of the peroxisome to the cytosol and mitochondria. The protein thus plays a role in lipid metabolism and fatty acid beta-oxidation. Alternatively spliced transcript variants have been described.[provided by RefSeq, Jan 2009]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1412361).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CROT	NM_021151.4	c.91T>A	p.Ser31Thr	missense_variant	3/18	ENST00000331536.8
CROT	NM_001143935.2	c.91T>A	p.Ser31Thr	missense_variant	3/19
CROT	NM_001243745.3	c.91T>A	p.Ser31Thr	missense_variant	3/4
CROT	XM_011516337.4	c.91T>A	p.Ser31Thr	missense_variant	3/18

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CROT	ENST00000331536.8	c.91T>A	p.Ser31Thr	missense_variant	3/18	1	NM_021151.4	P1
CROT	ENST00000412227.6	c.91T>A	p.Ser31Thr	missense_variant	3/4	1
CROT	ENST00000419147.6	c.91T>A	p.Ser31Thr	missense_variant	3/19	2
CROT	ENST00000442291.1	c.91T>A	p.Ser31Thr	missense_variant	2/17	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.97e-7 AC: 1 AN: 1433904 Hom.: 0 Cov.: 25 AF XY: 0.00000140 AC XY: 1 AN XY: 714160

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 9.16e-7

Gnomad4 OTH exome AF: 0.00

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

May 02, 2023

The c.91T>A (p.S31T) alteration is located in exon 3 (coding exon 1) of the CROT gene. This alteration results from a T to A substitution at nucleotide position 91, causing the serine (S) at amino acid position 31 to be replaced by a threonine (T). 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	0.076
BayesDel_addAF	Benign	-0.011	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	17
DANN	Benign	0.82
Eigen	Benign	-0.51
Eigen_PC	Benign	-0.25
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.73	T;T;T;T
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.14	T;T;T;T
MetaSVM	Benign	-0.80	T
MutationAssessor	Benign	-0.25	N;N;N;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	1.6	N;N;N;N
REVEL	Benign	0.19
Sift	Benign	1.0	T;T;T;T
Sift4G	Benign	1.0	T;T;T;T
Polyphen		0.0010	.;.;B;.
Vest4		0.45
MutPred		0.55		Loss of phosphorylation at S31 (P = 0.0598);Loss of phosphorylation at S31 (P = 0.0598);Loss of phosphorylation at S31 (P = 0.0598);Loss of phosphorylation at S31 (P = 0.0598);
MVP		0.60
MPC		0.025
ClinPred		0.072	T
GERP RS		4.7
Varity_R		0.16
gMVP		0.63

Splicing

Name	Calibrated prediction	Score	Prediction
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

Other links and lift over

dbSNP: rs1391974307; hg19: chr7-86978475;