7-87375649-A-T

Variant summary

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

The NM_021151.4(CROT):c.674A>T(p.His225Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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)
• Consequence: CROT NM_021151.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.65

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.29512572).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CROT	NM_021151.4	c.674A>T	p.His225Leu	missense_variant	8/18	ENST00000331536.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CROT	ENST00000331536.8	c.674A>T	p.His225Leu	missense_variant	8/18	1	NM_021151.4	P1
CROT	ENST00000419147.6	c.758A>T	p.His253Leu	missense_variant	9/19	2
CROT	ENST00000442291.1	c.674A>T	p.His225Leu	missense_variant	7/17	5
CROT	ENST00000469785.1	n.415A>T		non_coding_transcript_exon_variant	1/2	4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

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

Apr 19, 2023

The c.758A>T (p.H253L) alteration is located in exon 9 (coding exon 7) of the CROT gene. This alteration results from a A to T substitution at nucleotide position 758, causing the histidine (H) at amino acid position 253 to be replaced by a leucine (L). 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	0.15
BayesDel_addAF	Benign	0.011	T
BayesDel_noAF	Benign	-0.22
Cadd	Benign	15
Dann	Benign	0.92
Eigen	Benign	-0.63
Eigen_PC	Benign	-0.42
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.75	T;T;T
M_CAP	Benign	0.040	D
MetaRNN	Benign	0.30	T;T;T
MetaSVM	Benign	-0.90	T
MutationTaster	Benign	0.97	N;N;N
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-1.5	N;N;N
REVEL	Uncertain	0.31
Sift	Benign	0.078	T;T;T
Sift4G	Benign	0.34	T;T;T
Polyphen		0.0040	.;B;.
Vest4		0.46
MutPred		0.61		.;Loss of disorder (P = 0.0332);Loss of disorder (P = 0.0332);
MVP		0.57
MPC		0.033
ClinPred		0.17	T
GERP RS		6.0
Varity_R		0.098
gMVP		0.57

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: chr7-87004965;