chr16-74774639-G-T

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PS1PM1PM2PP3_StrongPP5_Moderate

The NM_024306.5(FA2H):c.117C>A(p.Phe39Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000000747 in 1,338,826 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 Pathogenic (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in ClinVar.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 7.5e-7 ( 0 hom. )

Consequence

FA2H
NM_024306.5 missense

Scores

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 4.67

Publications

1 publications found

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 Gene-Disease associations (from GenCC):

hereditary spastic paraplegia 35
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae), G2P

FA2H links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 14 ACMG points.

PS1

Transcript NM_024306.5 (FA2H) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.

PM1

In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in NM_024306.5

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.948

PP5

Variant 16-74774639-G-T is Pathogenic according to our data. Variant chr16-74774639-G-T is described in ClinVar as Pathogenic. ClinVar VariationId is 242579.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FA2H	NM_024306.5 link	c.117C>A	p.Phe39Leu	missense_variant	Exon 1 of 7	ENST00000219368.8	NP_077282.3	Q7L5A8-1
FA2H	XM_011523317.4 link	c.117C>A	p.Phe39Leu	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.117C>A	p.Phe39Leu	missense_variant	Exon 1 of 7	1	NM_024306.5	ENSP00000219368.3		Q7L5A8-1
FA2H	ENST00000567683.5 link	n.117C>A		non_coding_transcript_exon_variant	Exon 1 of 5	2		ENSP00000455126.1		H3BP32

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.47e-7

AC:

AN:

1338826

Hom.:

Cov.:

AF XY:

0.00000151

AC XY:

AN XY:

660618

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

27594

American (AMR)

AF:

0.00

AC:

AN:

30194

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23676

East Asian (EAS)

AF:

0.00

AC:

AN:

30040

South Asian (SAS)

AF:

0.00

AC:

AN:

73836

European-Finnish (FIN)

AF:

0.00

AC:

AN:

34082

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4186

European-Non Finnish (NFE)

AF:

9.44e-7

AC:

AN:

1059432

Other (OTH)

AF:

0.00

AC:

AN:

55786

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Spastic paraplegia

Pathogenic:1

May 05, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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. ClinVar contains an entry for this variant (Variation ID: 242579). This missense change has been observed in individual(s) with brain iron accumulation and/or hereditary spastic paraplegia (PMID: 25732363; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 39 of the FA2H protein (p.Phe39Leu). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.97

BayesDel_addAF

Pathogenic

0.41

BayesDel_noAF

Pathogenic

0.35

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.86

Eigen

Uncertain

0.65

Eigen_PC

Uncertain

0.57

FATHMM_MKL

Uncertain

0.77

LIST_S2

Benign

0.65

M_CAP

Pathogenic

0.99

MetaRNN

Pathogenic

0.95

MetaSVM

Uncertain

0.46

MutationAssessor

Pathogenic

3.0

PhyloP100

4.7

PrimateAI

Pathogenic

0.97

PROVEAN

Pathogenic

-5.0

REVEL

Pathogenic

0.96

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.51

MutPred

0.83

Loss of stability (P = 0.0631);

MVP

0.72

MPC

2.8

ClinPred

1.0

GERP RS

4.1

PromoterAI

0.021

Neutral

(source)

Varity_R

0.87

gMVP

0.89

Mutation Taster

=18/82

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over