rs978032580

Positions:

• chr16-74774662-G-A
• chr16-74774662-G-C
• chr16-74774662-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM2 PP3

The NM_024306.5(FA2H):​c.94C>T​(p.Arg32Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000778 in 1,285,852 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R32G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.8e-7 (0 hom.)
• Consequence: FA2H NM_024306.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.56

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 5 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 NM_024306.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.795

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FA2H	NM_024306.5	c.94C>T	p.Arg32Cys	missense_variant	1/7	ENST00000219368.8
FA2H	XM_011523317.4	c.94C>T	p.Arg32Cys	missense_variant	1/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FA2H	ENST00000219368.8	c.94C>T	p.Arg32Cys	missense_variant	1/7	1	NM_024306.5	P1
FA2H	ENST00000567683.5	c.94C>T	p.Arg32Cys	missense_variant, NMD_transcript_variant	1/5	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.78e-7 AC: 1 AN: 1285852 Hom.: 0 Cov.: 33 AF XY: 0.00000158 AC XY: 1 AN XY: 632382

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: 0.00

Gnomad4 OTH exome AF: 0.0000188

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Benign	-0.090
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.71	D
Eigen	Uncertain	0.22
Eigen_PC	Benign	0.13
FATHMM_MKL	Benign	0.60	D
LIST_S2	Benign	0.84	T
M_CAP	Pathogenic	0.99	D
MetaRNN	Pathogenic	0.80	D
MetaSVM	Uncertain	-0.21	T
MutationAssessor	Uncertain	2.6	M
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.95	D
PROVEAN	Uncertain	-3.8	D
REVEL	Uncertain	0.58
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.021	D
Polyphen		1.0	D
Vest4		0.52
MutPred		0.60		Loss of MoRF binding (P = 0.0054);
MVP		0.36
MPC		3.3
ClinPred		0.99	D
GERP RS		1.9
Varity_R		0.56
gMVP		0.80

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: rs978032580; hg19: chr16-74808560;