rs387907039

Positions:

chr16-74719071-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2PP3_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:4U:1

Conservation

PhyloP100: 6.59

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 Likely_pathogenic. Variant got 7 ACMG points.

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 submissions are: {Uncertain_significance=1, Pathogenic=1, Likely_pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FA2H	NM_024306.5 linkuse as main transcript	c.703C>T	p.Arg235Cys	missense_variant	5/7	ENST00000219368.8	NP_077282.3	Q7L5A8-1
FA2H	XM_011523317.4 linkuse as main transcript	c.703C>T	p.Arg235Cys	missense_variant	5/6		XP_011521619.1
FA2H	XM_011523319.3 linkuse as main transcript	c.463C>T	p.Arg155Cys	missense_variant	5/7		XP_011521621.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
FA2H	ENST00000219368.8 linkuse as main transcript	c.703C>T	p.Arg235Cys	missense_variant	5/7	1	NM_024306.5	ENSP00000219368.3	Q7L5A8-1
FA2H	ENST00000569949.1 linkuse as main transcript	c.505C>T	p.Arg169Cys	missense_variant	5/5	4		ENSP00000464576.1	J3QS89
FA2H	ENST00000567683.5 linkuse as main transcript	n.453C>T		non_coding_transcript_exon_variant	3/5	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

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251222

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135774

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 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:

0.00000821

AC:

AN:

1461712

Hom.:

Cov.:

AF XY:

0.00000688

AC XY:

AN XY:

727148

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000899

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152204

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74354

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:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hereditary spastic paraplegia 35

Pathogenic:3

Likely pathogenic, no assertion criteria provided	curation	Department Of Genetics, Sultan Qaboos University Hospital, Sultan Qaboos University	Jun 12, 2024	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Apr 01, 2010	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Dec 14, 2022	- -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jan 09, 2023

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) -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Nov 07, 2021

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

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;.

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

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

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