chr16-74774524-C-T

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_024306.5(FA2H):c.232G>A(p.Glu78Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000359 in 1,551,336 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00024 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00037 ( 0 hom. )

Consequence

FA2H
NM_024306.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:8

Conservation

PhyloP100: 7.05

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 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.09268516).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FA2H	NM_024306.5 link	c.232G>A	p.Glu78Lys	missense_variant	Exon 1 of 7	ENST00000219368.8	NP_077282.3	Q7L5A8-1
FA2H	XM_011523317.4 link	c.232G>A	p.Glu78Lys	missense_variant	Exon 1 of 6		XP_011521619.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FA2H	ENST00000219368.8 link	c.232G>A	p.Glu78Lys	missense_variant	Exon 1 of 7	1	NM_024306.5	ENSP00000219368.3		Q7L5A8-1
FA2H	ENST00000567683.5 link	n.232G>A		non_coding_transcript_exon_variant	Exon 1 of 5	2		ENSP00000455126.1		H3BP32

Frequencies

GnomAD3 genomes

AF:

0.000237

AC:

AN:

152190

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000327

Gnomad ASJ

AF:

0.000864

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000621

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000310

AC:

AN:

170850

Hom.:

AF XY:

0.000313

AC XY:

AN XY:

95738

show subpopulations

Gnomad AFR exome

AF:

0.000109

Gnomad AMR exome

AF:

0.000148

Gnomad ASJ exome

AF:

0.000426

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000592

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000390

Gnomad OTH exome

AF:

0.000236

GnomAD4 exome

AF:

0.000372

AC:

521

AN:

1399028

Hom.:

Cov.:

AF XY:

0.000375

AC XY:

260

AN XY:

692990

show subpopulations

Gnomad4 AFR exome

AF:

0.000129

Gnomad4 AMR exome

AF:

0.000129

Gnomad4 ASJ exome

AF:

0.000126

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000448

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000424

Gnomad4 OTH exome

AF:

0.000190

GnomAD4 genome

AF:

0.000236

AC:

AN:

152308

Hom.:

Cov.:

AF XY:

0.000269

AC XY:

AN XY:

74454

show subpopulations

Gnomad4 AFR

AF:

0.000120

Gnomad4 AMR

AF:

0.000327

Gnomad4 ASJ

AF:

0.000864

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000622

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000300

Hom.:

Bravo

AF:

0.000223

ExAC

AF:

0.000207

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:8

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hereditary spastic paraplegia 35

Pathogenic:1Uncertain:3

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This 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. -

Paris Brain Institute, Inserm - ICM

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 01, 2016

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Uncertain:2

Sep 01, 2021

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Reported previously with another FA2H variant in two unrelated patients in the published literature with complicated HSP, but it is not known whether the variants occurred on the same (in cis) or on different (in trans) chromosomes in both cases (Rattay et al., 2019); Reported previously with a variant on the opposite allele (in trans) in two patients in the published literature; one with early onset cerebellar ataxia (Shakya et al., 2019) and one with an immune phenotype (Klee et al., 2021); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 31135052, 31429931, 33144682) -

Mar 01, 2020

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Spastic paraplegia

Pathogenic:1

Oct 21, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 78 of the FA2H protein (p.Glu78Lys). This variant is present in population databases (rs527421775, gnomAD 0.06%). This missense change has been observed in individual(s) with FA2H related conditions (PMID: 31135052, 31429931). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 320501). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt FA2H protein function with a negative predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. -

not specified

Uncertain:1

Mar 06, 2022

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: FA2H c.232G>A (p.Glu78Lys) results in a conservative amino acid change located in the Cytochrome b5-like heme/steroid binding domain (IPR001199) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00031 in 170850 control chromosomes. The observed variant frequency is approximately 1.6 fold of the estimated maximal expected allele frequency for a pathogenic variant in FA2H causing Neurodegeneration With Brain Iron Accumulation phenotype (0.00019), suggesting that the variant may be benign. c.232G>A has been reported in the literature as a compound heterozygous genotype in settings of whole exome (WES) analysis among individuals presenting with early onset cerebellar ataxia (example, Shakya_2019), phenotypes from the neurodegeneration with brain iron accumulation (fatty acid hydroxylase- associated neurodegeneration, FAHN), hereditary spastic paraplegia (HSP type SPG35) and leukodystrophy (leukodystrophy with spasticity and dystonia) spectrum (example, Rattay_2019), and in an undiagnosed disease exome sequencing cohort (example, Klee_2021). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Inborn genetic diseases

Uncertain:1

Dec 16, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.232G>A (p.E78K) alteration is located in exon 1 (coding exon 1) of the FA2H gene. This alteration results from a G to A substitution at nucleotide position 232, causing the glutamic acid (E) at amino acid position 78 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Hereditary spastic paraplegia

Uncertain:1

Dec 12, 2016

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.48

BayesDel_addAF

Benign

-0.063

BayesDel_noAF

Uncertain

0.030

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.21

Eigen

Uncertain

0.19

Eigen_PC

Benign

0.20

FATHMM_MKL

Uncertain

0.85

LIST_S2

Uncertain

0.94

M_CAP

Pathogenic

0.46

MetaRNN

Benign

0.093

MetaSVM

Benign

-0.40

MutationAssessor

Benign

1.7

PrimateAI

Uncertain

0.73

PROVEAN

Benign

-0.51

REVEL

Uncertain

0.52

Sift

Benign

0.40

Sift4G

Benign

0.28

Polyphen

0.89

Vest4

0.38

MutPred

0.46

Gain of MoRF binding (P = 0.0138);

MVP

0.21

MPC

2.4

ClinPred

0.069

GERP RS

3.9

Varity_R

0.56

gMVP

0.66

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.

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