rs387907039

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM1PM2PP3_StrongPP5

The NM_024306.5(FA2H):c.703C>T(p.Arg235Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000867 in 1,613,916 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).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000082 ( 0 hom. )

Consequence

FA2H
NM_024306.5 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 6.59

Publications

9 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: Likely_pathogenic. The variant received 9 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_024306.5

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.987

PP5

Variant 16-74719071-G-A is Pathogenic according to our data. Variant chr16-74719071-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 30870.We mark this variant Likely_pathogenic, oryginal submission is: [Conflicting_classifications_of_pathogenicity].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FA2H	NM_024306.5 link	c.703C>T	p.Arg235Cys	missense_variant	Exon 5 of 7	ENST00000219368.8	NP_077282.3	Q7L5A8-1
FA2H	XM_011523317.4 link	c.703C>T	p.Arg235Cys	missense_variant	Exon 5 of 6		XP_011521619.1
FA2H	XM_011523319.3 link	c.463C>T	p.Arg155Cys	missense_variant	Exon 5 of 7		XP_011521621.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
FA2H	ENST00000219368.8 link	c.703C>T	p.Arg235Cys	missense_variant	Exon 5 of 7	1	NM_024306.5	ENSP00000219368.3	Q7L5A8-1
FA2H	ENST00000569949.1 link	c.505C>T	p.Arg169Cys	missense_variant	Exon 5 of 5	4		ENSP00000464576.1	J3QS89
FA2H	ENST00000567683.5 link	n.453C>T		non_coding_transcript_exon_variant	Exon 3 of 5	2		ENSP00000455126.1	H3BP32

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152204

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:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000398

AC:

AN:

251222

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS 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:

0.00000821

AC:

AN:

1461712

Hom.:

Cov.:

AF XY:

0.00000688

AC XY:

AN XY:

727148

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53250

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000899

AC:

AN:

1112000

Other (OTH)

AF:

0.00

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.546

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

AF:

0.0000131

AC:

AN:

152204

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74354

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41456

American (AMR)

AF:

0.00

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.000207

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68040

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.625

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.00

Hom.:

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

Apr 01, 2010

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Dec 14, 2022

Revvity Omics, Revvity

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 12, 2024

Department Of Genetics, Sultan Qaboos University Hospital, Sultan Qaboos University

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:curation

- -

not provided

Pathogenic:1

Jan 09, 2023

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Published functional studies demonstrate a reduction in 2-hydroxylated ceramide activity (Dick et al., 2010); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 26944241, 33144682, 20104589) -

Intellectual disability

Pathogenic:1

Apr 03, 2020

Cambridge Genomics Laboratory, East Genomic Laboratory Hub, NHS Genomic Medicine Service

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Uncertain:1

Nov 07, 2021

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.703C>T (p.Arg235Cys) results in a non-conservative amino acid change located in the Fatty acid hydroxylase domain (IPR006694) of 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 4e-06 in 251222 control chromosomes. c.703C>T has been reported in the literature as a homozygous genotype in one individual affected with autosomal recessive form of HSP (SPG35) (example, Dick_2010). These data indicate that the variant may be associated with disease. However, a subsequent study has reported that cerebral iron accumulation is not a major feature of FA2H associated autosomal recessive spastic paraplegia (SPG35) (Marelli_2015). Therefore, these report(s) do not provide unequivocal conclusions about association of the variant with Neurodegeneration with brain iron accumulation. At least one publication reports experimental evidence evaluating an impact on protein function (Dick_2010). The most pronounced variant effect results in >50%-90% of normal levels of hydroxylated ceramides. One clinical diagnostic laboratory (most likely the originator of the reported individual, Dick_2010) has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.42

BayesDel_addAF

Pathogenic

0.41

BayesDel_noAF

Pathogenic

0.44

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.93

D;D

Eigen

Pathogenic

0.95

Eigen_PC

Pathogenic

0.84

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.97

D;D

M_CAP

Pathogenic

0.41

MetaRNN

Pathogenic

0.99

D;D

MetaSVM

Pathogenic

0.86

MutationAssessor

Pathogenic

4.2

H;.

PhyloP100

6.6

PrimateAI

Uncertain

0.71

PROVEAN

Pathogenic

-7.5

D;.

REVEL

Pathogenic

0.84

Sift

Pathogenic

0.0

D;.

Sift4G

Pathogenic

0.0010

D;.

Polyphen

1.0

D;.

Vest4

1.0

MutPred

0.95

Loss of disorder (P = 0.1558);.;

MVP

0.91

MPC

0.96

ClinPred

1.0

GERP RS

4.4

Varity_R

0.89

gMVP

0.96

Mutation Taster

=5/95

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over