rs121918217

Variant names:

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

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PS3 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). ClinVar reports functional evidence for this variant: "SCV005088805: "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".

• 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), ClinGen, G2P

ACMG classification

Our verdict: Pathogenic. The variant received 13 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV005088805: "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
• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 uncertain 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 VariationId is 1044.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024306.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FA2H	NM_024306.5	MANE Select	c.103G>T	p.Asp35Tyr	missense	Exon 1 of 7	NP_077282.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FA2H	ENST00000219368.8	TSL:1 MANE Select	c.103G>T	p.Asp35Tyr	missense	Exon 1 of 7	ENSP00000219368.3	Q7L5A8-1
	FA2H	ENST00000888352.1		c.103G>T	p.Asp35Tyr	missense	Exon 1 of 7	ENSP00000558411.1
	FA2H	ENST00000888351.1		c.103G>T	p.Asp35Tyr	missense	Exon 1 of 7	ENSP00000558410.1

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

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
3	1	-	Hereditary spastic paraplegia 35 (4)

Computational scores

Source: dbNSFP v4.9

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;