rs387907040

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PP3_ModeratePP5

The NM_024306.5(FA2H):c.460C>T(p.Arg154Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000929 in 1,614,020 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R154H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000096 ( 0 hom. )

Consequence

FA2H
NM_024306.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5U:1

Conservation

PhyloP100: 6.03

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]

FA2H links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 5 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.895

PP5

Variant 16-74727290-G-A is Pathogenic according to our data. Variant chr16-74727290-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 30872.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=3, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
FA2H	NM_024306.5 linkuse as main transcript	c.460C>T	p.Arg154Cys	missense_variant	3/7	ENST00000219368.8
FA2H	XM_011523317.4 linkuse as main transcript	c.460C>T	p.Arg154Cys	missense_variant	3/6
FA2H	XM_011523319.3 linkuse as main transcript	c.220C>T	p.Arg74Cys	missense_variant	3/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FA2H	ENST00000219368.8 linkuse as main transcript	c.460C>T	p.Arg154Cys	missense_variant	3/7	1	NM_024306.5	P1	Q7L5A8-1
FA2H	ENST00000569949.1 linkuse as main transcript	c.262C>T	p.Arg88Cys	missense_variant	3/5	4
FA2H	ENST00000567683.5 linkuse as main transcript	c.364-8130C>T		intron_variant, NMD_transcript_variant		2

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152172

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000239

AC:

AN:

251280

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135842

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000145

Gnomad ASJ exome

AF:

0.0000992

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:

0.00000958

AC:

AN:

1461848

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

727222

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000112

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000540

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152172

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74342

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hereditary spastic paraplegia 35

Pathogenic:3

Likely pathogenic, no assertion criteria provided	clinical testing	Genomics England Pilot Project, Genomics England	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 01, 2010	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genomic Research Center, Shahid Beheshti University of Medical Sciences	May 03, 2020	- -

Spastic paraplegia

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jul 27, 2022

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 154 of the FA2H protein (p.Arg154Cys). This variant is present in population databases (rs387907040, gnomAD 0.01%). This missense change has been observed in individuals with clinical features of FA2H-related conditions (PMID: 20853438, 27217339, 31135052, 32907636). ClinVar contains an entry for this variant (Variation ID: 30872). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt FA2H protein function. Studies have shown that this missense change alters FA2H gene expression (PMID: 20853438). For these reasons, this variant has been classified as Pathogenic. -

Neurodegeneration with brain iron accumulation

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jun 16, 2023

Variant summary: FA2H c.460C>T (p.Arg154Cys) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 251280 control chromosomes. c.460C>T has been reported in the literature in multiple individuals affected with FA2H-related conditions (e.g., Kruer_2010, Rattay_2019, Tsang_2020). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence demonstrating reduced levels of protein expression in mutant cells, indicating reduced stability of the mRNA or protein product (Kruer_2010). The following publications have been ascertained in the context of this evaluation (PMID: 20853438, 31135052, 32907636). Three ClinVar submitters have submitted clinical-significance assessments for this variant to ClinVar after 2014. One submitter classified the variant as a variant on uncertain significance, while two submitter classified it as likely pathogenic/pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Nov 17, 2022

In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 29376581, 34758253, 24299421, 20853438, 29423566, 25141825, 31589614, 32907636, 34852264, 31837835, 27217339, 31135052) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.42

BayesDel_addAF

Pathogenic

0.37

BayesDel_noAF

Pathogenic

0.56

Cadd

Pathogenic

Dann

Pathogenic

1.0

DEOGEN2

Uncertain

0.78

D;T

Eigen

Pathogenic

0.88

Eigen_PC

Pathogenic

0.81

FATHMM_MKL

Uncertain

0.85

LIST_S2

Uncertain

0.96

D;D

M_CAP

Pathogenic

0.61

MetaRNN

Pathogenic

0.90

D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.5

H;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.71

PROVEAN

Pathogenic

-7.9

D;.

REVEL

Pathogenic

0.94

Sift

Pathogenic

0.0

D;.

Sift4G

Pathogenic

0.0

D;.

Polyphen

1.0

D;.

Vest4

0.98

MutPred

0.68

Gain of catalytic residue at L155 (P = 0.0135);.;

MVP

0.95

MPC

0.96

ClinPred

0.94

GERP RS

5.3

Varity_R

0.85

gMVP

0.83

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

LitVar

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

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over