chr16-74719002-C-T

Position:

• chr16-74719002-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_024306.5(FA2H):​c.772G>A​(p.Gly258Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,518 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 Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: FA2H NM_024306.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 7.69

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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.933

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FA2H	NM_024306.5	c.772G>A	p.Gly258Ser	missense_variant	5/7	ENST00000219368.8	NP_077282.3
FA2H	XM_011523317.4	c.772G>A	p.Gly258Ser	missense_variant	5/6		XP_011521619.1
FA2H	XM_011523319.3	c.532G>A	p.Gly178Ser	missense_variant	5/7		XP_011521621.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FA2H	ENST00000219368.8	c.772G>A	p.Gly258Ser	missense_variant	5/7	1	NM_024306.5	ENSP00000219368.3
FA2H	ENST00000569949.1	c.574G>A	p.Gly192Ser	missense_variant	5/5	4		ENSP00000464576.1
FA2H	ENST00000567683.5	n.*51G>A		non_coding_transcript_exon_variant	3/5	2		ENSP00000455126.1
FA2H	ENST00000567683.5	n.*51G>A		3_prime_UTR_variant	3/5	2		ENSP00000455126.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000159 AC: 4 AN: 250900 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135632

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000578

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: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461518 Hom.: 0 Cov.: 33 AF XY: 0.00000275 AC XY: 2 AN XY: 727016

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000447

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: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000372 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.0000247 AC: 3

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Spastic paraplegia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 11, 2022

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt FA2H protein function. ClinVar contains an entry for this variant (Variation ID: 547856). This missense change has been observed in individual(s) with clinical features of FA2H related conditions (PMID: 31130284). This variant is present in population databases (rs774693133, gnomAD 0.006%). This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 258 of the FA2H protein (p.Gly258Ser). -

Hereditary spastic paraplegia 35 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Mayo Clinic Laboratories, Mayo Clinic

Jul 01, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.84
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.53
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.92	D;D
Eigen	Pathogenic	0.95
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.92	D;T
M_CAP	Pathogenic	0.34	D
MetaRNN	Pathogenic	0.92	D;D
MetaSVM	Pathogenic	0.91	D
MutationAssessor	Pathogenic	4.2	H;.
PrimateAI	Uncertain	0.57	T
PROVEAN	Pathogenic	-5.6	D;.
REVEL	Pathogenic	0.91
Sift	Pathogenic	0.0	D;.
Sift4G	Pathogenic	0.0	D;.
Polyphen		1.0	D;.
Vest4		0.96
MVP		0.91
MPC		0.81
ClinPred		1.0	D
GERP RS		4.8
Varity_R		0.92
gMVP		0.91

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: rs774693133; hg19: chr16-74752900; COSMIC: COSV54727410; COSMIC: COSV54727410;