1-46934294-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_000778.4(CYP4A11):​c.970G>A​(p.Asp324Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00000683 in 1,611,712 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: 𝑓 0.000013 ( 0 hom., cov: 28)
Exomes 𝑓: 0.0000062 ( 0 hom. )

Consequence

CYP4A11
NM_000778.4 missense

Scores

6
8
5

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.10
Variant links:
Genes affected
CYP4A11 (HGNC:2642): (cytochrome P450 family 4 subfamily A member 11) This gene encodes a member of the cytochrome P450 superfamily of enzymes. The cytochrome P450 proteins are monooxygenases which catalyze many reactions involved in drug metabolism and synthesis of cholesterol, steroids and other lipids. This protein localizes to the endoplasmic reticulum and hydroxylates medium-chain fatty acids such as laurate and myristate. Multiple transcript variants have been found for this gene. [provided by RefSeq, Jan 2016]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.952

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CYP4A11NM_000778.4 linkc.970G>A p.Asp324Asn missense_variant Exon 8 of 12 ENST00000310638.9 NP_000769.2 Q02928-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CYP4A11ENST00000310638.9 linkc.970G>A p.Asp324Asn missense_variant Exon 8 of 12 1 NM_000778.4 ENSP00000311095.4 Q02928-1
CYP4A11ENST00000465874.5 linkn.609-289G>A intron_variant Intron 5 of 7 2 ENSP00000476368.1 V9GY41

Frequencies

GnomAD3 genomes
AF:
0.0000133
AC:
2
AN:
150510
Hom.:
0
Cov.:
28
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000662
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000148
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000401
AC:
1
AN:
249240
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
134664
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000290
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:
0.00000616
AC:
9
AN:
1461202
Hom.:
0
Cov.:
33
AF XY:
0.00000688
AC XY:
5
AN XY:
726852
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000224
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:
0.00000630
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.0000133
AC:
2
AN:
150510
Hom.:
0
Cov.:
28
AF XY:
0.0000273
AC XY:
2
AN XY:
73324
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.0000662
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000148
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000712
Hom.:
0

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Jan 03, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.970G>A (p.D324N) alteration is located in exon 8 (coding exon 8) of the CYP4A11 gene. This alteration results from a G to A substitution at nucleotide position 970, causing the aspartic acid (D) at amino acid position 324 to be replaced by an asparagine (N). 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
0.85
BayesDel_addAF
Benign
-0.043
T
BayesDel_noAF
Benign
-0.22
CADD
Uncertain
24
DANN
Pathogenic
1.0
DEOGEN2
Uncertain
0.65
D;.;.
Eigen
Uncertain
0.66
Eigen_PC
Uncertain
0.58
FATHMM_MKL
Pathogenic
0.97
D
LIST_S2
Uncertain
0.88
D;D;D
M_CAP
Benign
0.023
T
MetaRNN
Pathogenic
0.95
D;D;D
MetaSVM
Uncertain
0.35
D
MutationAssessor
Pathogenic
4.7
H;.;.
PrimateAI
Uncertain
0.50
T
PROVEAN
Pathogenic
-4.4
D;D;D
REVEL
Uncertain
0.57
Sift
Benign
0.033
D;D;D
Sift4G
Uncertain
0.017
D;D;D
Polyphen
0.99
D;.;.
Vest4
0.48
MutPred
0.93
Gain of helix (P = 0.1736);.;Gain of helix (P = 0.1736);
MVP
0.88
MPC
0.23
ClinPred
0.98
D
GERP RS
4.3
Varity_R
0.45
gMVP
0.48

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1488482611; hg19: chr1-47399966; API