rs121918217

Variant names:

• chr16-74774653-C-A
• rs121918217
• NM_024306.5:c.103G>T

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM1 PM2 PP3_Strong PP5

The NM_024306.5(FA2H):​c.103G>T​(p.Asp35Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.000000765 in 1,307,134 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: not found (cov: 33)
  • Exomes 𝑓: 7.7e-7 (0 hom.)
• Consequence: FA2H NM_024306.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:1
• Conservation: PhyloP100: 6.82
• Publications: 8 publications found

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

ACMG classification

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

• PM1: In a domain Cytochrome b5 heme-binding (size 78) in uniprot entity FA2H_HUMAN there are 9 pathogenic changes around while only 1 benign (90%) in NM_024306.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.992
• PP5: Variant 16-74774653-C-A is Pathogenic according to our data. Variant chr16-74774653-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1044.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	c.103G>T	p.Asp35Tyr	missense_variant	Exon 1 of 7	ENST00000219368.8	NP_077282.3
FA2H	XM_011523317.4	c.103G>T	p.Asp35Tyr	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	c.103G>T	p.Asp35Tyr	missense_variant	Exon 1 of 7	1	NM_024306.5	ENSP00000219368.3
FA2H	ENST00000567683.5	n.103G>T		non_coding_transcript_exon_variant	Exon 1 of 5	2		ENSP00000455126.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.65e-7 AC: 1 AN: 1307134 Hom.: 0 Cov.: 33 AF XY: 0.00000155 AC XY: 1 AN XY: 643836

African (AFR) AF: 0.00 AC: 0 AN: 26878

American (AMR) AF: 0.00 AC: 0 AN: 25936

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22982

East Asian (EAS) AF: 0.00 AC: 0 AN: 28378

South Asian (SAS) AF: 0.00 AC: 0 AN: 69390

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33248

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4022

European-Non Finnish (NFE) AF: 9.60e-7 AC: 1 AN: 1042028

Other (OTH) AF: 0.00 AC: 0 AN: 54272

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000688 Hom.: 0

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary spastic paraplegia 35 Pathogenic:3 Uncertain:1

Jan 30, 2020

Breakthrough Genomics, Breakthrough Genomics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is predicted to be damaging by in-silico missense prediction tools (SIFT and Polyphen2). The variant was previously reported in a consanguineous Arab-Muslim family (as c.103G→T and D35Y in the article) in the homozygous state and the patient was diagnosed with Leukodystrophy with Spastic Paraparesis and Dystonia [PMID: 19068277, 21592092, 24299421]. In-vitro functional studies revealed that the cells harboring the p.Asp35Tyr variant exhibited a significant reduction in endogenous FA2H enzymatic activity when compared to wild type cells suggesting its loss-of-function [PMID: 19068277]. -

Sep 06, 2022

Revvity Omics, Revvity

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 23, 2023

3billion

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is not observed in the gnomAD v2.1.1 dataset. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.94; 3Cnet: 0.94). Same nucleotide change resulting in same amino acid change has been previously reported to be associated with FA2H -related disorder (ClinVar ID: VCV000001044 / PMID: 19068277). The variant has been reported to co-segregate with the disease in at least one similarly affected relative/individual in the same family or similarly affected unrelated family (PMID: 19068277). However, the evidence of pathogenicity is insufficient at this time. Therefore, this variant is classified as VUS according to the recommendation of ACMG/AMP guideline. -

Nov 01, 2008

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.79
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.48
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.89	D
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.78	T
M_CAP	Pathogenic	0.99	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.5	H
PhyloP100		6.8
PrimateAI	Pathogenic	0.96	D
PROVEAN	Pathogenic	-6.0	D
REVEL	Pathogenic	0.94
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.97
MutPred		0.95		Loss of disorder (P = 0.0475);
MVP		0.90
MPC		3.2
ClinPred		1.0	D
GERP RS		4.0
PromoterAI		-0.082	Neutral
Varity_R		0.97
gMVP		0.96
Mutation Taster		=181/119	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs121918217; hg19: chr16-74808551;