7-87381952-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_021151.4(CROT):c.1021T>C(p.Tyr341His) variant causes a missense change. The variant allele was found at a frequency of 0.0000123 in 1,458,944 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: 33)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: CROT NM_021151.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.69

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]

ABCB4 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.778

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CROT	NM_021151.4	c.1021T>C	p.Tyr341His	missense_variant	11/18	ENST00000331536.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CROT	ENST00000331536.8	c.1021T>C	p.Tyr341His	missense_variant	11/18	1	NM_021151.4	P1
CROT	ENST00000419147.6	c.1105T>C	p.Tyr369His	missense_variant	12/19	2
CROT	ENST00000442291.1	c.1021T>C	p.Tyr341His	missense_variant	10/17	5
CROT	ENST00000479014.1	n.226T>C		non_coding_transcript_exon_variant	3/4	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.0000123 AC: 18 AN: 1458944 Hom.: 0 Cov.: 29 AF XY: 0.0000165 AC XY: 12 AN XY: 725656

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: 0.0000162

Gnomad4 OTH exome AF: 0.00

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

Dec 06, 2022

The c.1105T>C (p.Y369H) alteration is located in exon 12 (coding exon 10) of the CROT gene. This alteration results from a T to C substitution at nucleotide position 1105, causing the tyrosine (Y) at amino acid position 369 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	Benign	0.19
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.050
Cadd	Uncertain	25
Dann	Uncertain	1.0
Eigen	Benign	-0.14
Eigen_PC	Benign	-0.061
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.84	T;T;T
M_CAP	Benign	0.043	D
MetaRNN	Pathogenic	0.78	D;D;D
MetaSVM	Uncertain	-0.15	T
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.55	T
PROVEAN	Uncertain	-2.9	D;D;D
REVEL	Uncertain	0.60
Sift	Benign	0.12	T;T;T
Sift4G	Uncertain	0.0060	D;D;D
Polyphen		0.21	.;B;.
Vest4		0.75
MutPred		0.59		.;Loss of methylation at K345 (P = 0.0539);Loss of methylation at K345 (P = 0.0539);
MVP		0.68
MPC		0.051
ClinPred		0.97	D
GERP RS		4.2
Varity_R		0.44
gMVP		0.76

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: rs898097814; hg19: chr7-87011268;