rs121918217

Positions:

• chr16-74774653-C-A

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PP3_Strong PP5

The ENST00000219368.8(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 ENST00000219368.8 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:1
• Conservation: PhyloP100: 6.82

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in ENST00000219368.8
• 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 submissions are: {Likely_pathogenic=1, Pathogenic=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FA2H	NM_024306.5	c.103G>T	p.Asp35Tyr	missense_variant	1/7	ENST00000219368.8	NP_077282.3
FA2H	XM_011523317.4	c.103G>T	p.Asp35Tyr	missense_variant	1/6		XP_011521619.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FA2H	ENST00000219368.8	c.103G>T	p.Asp35Tyr	missense_variant	1/7	1	NM_024306.5	ENSP00000219368	P1
FA2H	ENST00000567683.5	c.103G>T	p.Asp35Tyr	missense_variant, NMD_transcript_variant	1/5	2		ENSP00000455126

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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.60e-7

Gnomad4 OTH exome AF: 0.00

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

Pathogenic, criteria provided, single submitter	clinical testing	Breakthrough Genomics, Breakthrough Genomics	Jan 30, 2020	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]. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Sep 06, 2022	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 01, 2008	- -
Uncertain significance, criteria provided, single submitter	clinical testing	3billion	Feb 23, 2023	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. -

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
MutationTaster	Benign	1.0	A;A
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
Varity_R		0.97
gMVP		0.96

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

Other links and lift over

dbSNP: rs121918217; hg19: chr16-74808551;