rs141854925

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_024306.5(FA2H):​c.1112C>T​(p.Thr371Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000189 in 1,560,598 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00015 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00019 ( 0 hom. )

Consequence

FA2H
NM_024306.5 missense

Scores

19

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:1

Conservation

PhyloP100: 0.0940
Variant links:
Genes affected
FA2H (HGNC:21197): (fatty acid 2-hydroxylase) This gene encodes a protein that catalyzes the synthesis of 2-hydroxysphingolipids, a subset of sphingolipids that contain 2-hydroxy fatty acids. Sphingolipids play roles in many cellular processes and their structural diversity arises from modification of the hydrophobic ceramide moiety, such as by 2-hydroxylation of the N-acyl chain, and the existence of many different head groups. Mutations in this gene have been associated with leukodystrophy dysmyelinating with spastic paraparesis with or without dystonia.[provided by RefSeq, Mar 2010]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.011379689).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
FA2HNM_024306.5 linkuse as main transcriptc.1112C>T p.Thr371Met missense_variant 7/7 ENST00000219368.8 NP_077282.3
FA2HXM_011523319.3 linkuse as main transcriptc.872C>T p.Thr291Met missense_variant 7/7 XP_011521621.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
FA2HENST00000219368.8 linkuse as main transcriptc.1112C>T p.Thr371Met missense_variant 7/71 NM_024306.5 ENSP00000219368 P1Q7L5A8-1
FA2HENST00000562145.1 linkuse as main transcriptn.833C>T non_coding_transcript_exon_variant 2/21
FA2HENST00000567683.5 linkuse as main transcriptc.*391C>T 3_prime_UTR_variant, NMD_transcript_variant 5/52 ENSP00000455126

Frequencies

GnomAD3 genomes
AF:
0.000151
AC:
23
AN:
152208
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000724
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00115
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000207
Gnomad FIN
AF:
0.0000942
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000191
Gnomad OTH
AF:
0.000478
GnomAD3 exomes
AF:
0.000286
AC:
49
AN:
171506
Hom.:
0
AF XY:
0.000352
AC XY:
32
AN XY:
90782
show subpopulations
Gnomad AFR exome
AF:
0.000101
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.000801
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.000721
Gnomad FIN exome
AF:
0.0000620
Gnomad NFE exome
AF:
0.000288
Gnomad OTH exome
AF:
0.000629
GnomAD4 exome
AF:
0.000193
AC:
272
AN:
1408390
Hom.:
0
Cov.:
30
AF XY:
0.000220
AC XY:
153
AN XY:
695796
show subpopulations
Gnomad4 AFR exome
AF:
0.0000312
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.000555
Gnomad4 EAS exome
AF:
0.0000273
Gnomad4 SAS exome
AF:
0.000764
Gnomad4 FIN exome
AF:
0.0000798
Gnomad4 NFE exome
AF:
0.000161
Gnomad4 OTH exome
AF:
0.000274
GnomAD4 genome
AF:
0.000151
AC:
23
AN:
152208
Hom.:
0
Cov.:
32
AF XY:
0.000134
AC XY:
10
AN XY:
74358
show subpopulations
Gnomad4 AFR
AF:
0.0000724
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00115
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000207
Gnomad4 FIN
AF:
0.0000942
Gnomad4 NFE
AF:
0.000191
Gnomad4 OTH
AF:
0.000478
Alfa
AF:
0.000255
Hom.:
0
Bravo
AF:
0.000185
ESP6500AA
AF:
0.000228
AC:
1
ESP6500EA
AF:
0.000700
AC:
6
ExAC
AF:
0.000196
AC:
23
Asia WGS
AF:
0.000577
AC:
2
AN:
3478

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:4Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:2
Uncertain significance, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenJul 01, 2021- -
Uncertain significance, criteria provided, single submitterclinical testingAthena DiagnosticsJan 16, 2018- -
Hereditary spastic paraplegia 35 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 2018This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Hereditary spastic paraplegia Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingGenome Diagnostics Laboratory, The Hospital for Sick ChildrenNov 18, 2020- -
Spastic paraplegia Benign:1
Likely benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 21, 2024- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.061
BayesDel_addAF
Benign
-0.39
T
BayesDel_noAF
Benign
-0.43
CADD
Benign
7.8
DANN
Benign
0.96
DEOGEN2
Benign
0.12
T
Eigen
Benign
-0.94
Eigen_PC
Benign
-0.92
FATHMM_MKL
Benign
0.045
N
LIST_S2
Benign
0.54
T
M_CAP
Benign
0.037
D
MetaRNN
Benign
0.011
T
MetaSVM
Benign
-0.79
T
MutationAssessor
Benign
0.57
N
MutationTaster
Benign
1.0
N;N
PrimateAI
Benign
0.29
T
PROVEAN
Benign
-0.11
N
REVEL
Benign
0.12
Sift
Benign
0.46
T
Sift4G
Benign
0.29
T
Polyphen
0.079
B
Vest4
0.055
MVP
0.19
MPC
0.23
ClinPred
0.0073
T
GERP RS
-0.41
Varity_R
0.012
gMVP
0.55

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: rs141854925; hg19: chr16-74748095; COSMIC: COSV99548069; COSMIC: COSV99548069; API