rs990027087

chr16-74774583-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_024306.5(FA2H):c.173T>C(p.Ile58Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000000722 in 1,384,346 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: FA2H NM_024306.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 6.20

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.

• PM1: In a domain Cytochrome b5 heme-binding (size 78) in uniprot entity FA2H_HUMAN there are 10 pathogenic changes around while only 2 benign (83%) in NM_024306.5
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FA2H	NM_024306.5	c.173T>C	p.Ile58Thr	missense_variant	1/7	ENST00000219368.8
FA2H	XM_011523317.4	c.173T>C	p.Ile58Thr	missense_variant	1/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FA2H	ENST00000219368.8	c.173T>C	p.Ile58Thr	missense_variant	1/7	1	NM_024306.5	P1
FA2H	ENST00000567683.5	c.173T>C	p.Ile58Thr	missense_variant, NMD_transcript_variant	1/5	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.22e-7 AC: 1 AN: 1384346 Hom.: 0 Cov.: 33 AF XY: 0.00000146 AC XY: 1 AN XY: 685040

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: 9.23e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

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

Invitae

Oct 20, 2021

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 missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). This missense change has been observed in individual(s) with FA2H-related conditions (Invitae). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the ExAC database. This sequence change replaces isoleucine with threonine at codon 58 of the FA2H protein (p.Ile58Thr). The isoleucine residue is moderately conserved and there is a moderate physicochemical difference between isoleucine and threonine. -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 28, 2023

The c.173T>C (p.I58T) alteration is located in exon 1 (coding exon 1) of the FA2H gene. This alteration results from a T to C substitution at nucleotide position 173, causing the isoleucine (I) at amino acid position 58 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.72
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.060
Cadd	Uncertain	25
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.66	D
Eigen	Benign	0.0091
Eigen_PC	Benign	0.098
FATHMM_MKL	Benign	0.60	D
LIST_S2	Benign	0.74	T
M_CAP	Pathogenic	0.68	D
MetaRNN	Uncertain	0.60	D
MetaSVM	Uncertain	-0.17	T
MutationAssessor	Uncertain	2.7	M
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.79	T
PROVEAN	Uncertain	-2.7	D
REVEL	Uncertain	0.58
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.017	D
Polyphen		0.042	B
Vest4		0.52
MutPred		0.58		Gain of disorder (P = 0.0273);
MVP		0.81
MPC		2.3
ClinPred		0.97	D
GERP RS		4.1
Varity_R		0.56
gMVP		0.76

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: rs990027087; hg19: chr16-74808481;