rs863224870

Positions:

• chr16-74726321-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Moderate PP5_Moderate

The NM_024306.5(FA2H):​c.517C>T​(p.Pro173Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: FA2H NM_024306.5 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 2.98

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 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.856
• PP5: Variant 16-74726321-G-A is Pathogenic according to our data. Variant chr16-74726321-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 216927.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FA2H	NM_024306.5	c.517C>T	p.Pro173Ser	missense_variant	4/7	ENST00000219368.8	NP_077282.3
FA2H	XM_011523317.4	c.517C>T	p.Pro173Ser	missense_variant	4/6		XP_011521619.1
FA2H	XM_011523319.3	c.277C>T	p.Pro93Ser	missense_variant	4/7		XP_011521621.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FA2H	ENST00000219368.8	c.517C>T	p.Pro173Ser	missense_variant	4/7	1	NM_024306.5	ENSP00000219368.3
FA2H	ENST00000569949.1	c.319C>T	p.Pro107Ser	missense_variant	4/5	4		ENSP00000464576.1
FA2H	ENST00000567683.5	n.364-7161C>T		intron_variant		2		ENSP00000455126.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary spastic paraplegia 35 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

UCLA Clinical Genomics Center, UCLA

Apr 15, 2014

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.50
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.040
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.82	D;D
Eigen	Uncertain	0.67
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.84	T;D
M_CAP	Pathogenic	0.40	D
MetaRNN	Pathogenic	0.86	D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.7	H;.
PrimateAI	Benign	0.44	T
PROVEAN	Pathogenic	-6.0	D;.
REVEL	Pathogenic	0.69
Sift	Uncertain	0.021	D;.
Sift4G	Uncertain	0.027	D;.
Polyphen		0.98	D;.
Vest4		0.66
MutPred		0.71		Gain of sheet (P = 0.1451);.;
MVP		0.85
MPC		0.79
ClinPred		0.99	D
GERP RS		5.7
Varity_R		0.23
gMVP		0.79

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: rs863224870; hg19: chr16-74760219;