rs147632811

Variant names:

• chr16-74740048-C-A
• rs147632811
• NM_024306.5:c.338G>T

Your query was ambiguous. Multiple possible variants found:

• chr16-74740048-C-A
• chr16-74740048-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_024306.5(FA2H):​c.338G>T​(p.Arg113Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,638 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/23 in silico tools predict a benign 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. R113Q) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: FA2H NM_024306.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.827

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

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.10782555).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FA2H	NM_024306.5	c.338G>T	p.Arg113Leu	missense_variant	Exon 2 of 7	ENST00000219368.8	NP_077282.3
FA2H	XM_011523317.4	c.338G>T	p.Arg113Leu	missense_variant	Exon 2 of 6		XP_011521619.1
FA2H	XM_011523319.3	c.98G>T	p.Arg33Leu	missense_variant	Exon 2 of 7		XP_011521621.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FA2H	ENST00000219368.8	c.338G>T	p.Arg113Leu	missense_variant	Exon 2 of 7	1	NM_024306.5	ENSP00000219368.3
FA2H	ENST00000569949.1	c.140G>T	p.Arg47Leu	missense_variant	Exon 2 of 5	4		ENSP00000464576.1
FA2H	ENST00000567683.5	n.338G>T		non_coding_transcript_exon_variant	Exon 2 of 5	2		ENSP00000455126.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461638 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727138

Gnomad4 AFR exome AF: 0.00 AC: 0 AN: 33474

Gnomad4 AMR exome AF: 0.00 AC: 0 AN: 44724

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 26132

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 39694

Gnomad4 SAS exome AF: 0.00 AC: 0 AN: 86248

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 53416

Gnomad4 NFE exome AF: 8.99e-7 AC: 1 AN: 1111800

Gnomad4 Remaining exome AF: 0.00 AC: 0 AN: 60382

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.033	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	15
DANN	Uncertain	0.99
DEOGEN2	Benign	0.20	T;T
Eigen	Benign	-0.65
Eigen_PC	Benign	-0.60
FATHMM_MKL	Benign	0.26	N
LIST_S2	Benign	0.73	T;T
M_CAP	Benign	0.051	D
MetaRNN	Benign	0.11	T;T
MetaSVM	Benign	-0.75	T
MutationAssessor	Benign	1.8	L;.
PrimateAI	Benign	0.21	T
PROVEAN	Benign	-1.3	N;.
REVEL	Benign	0.12
Sift	Benign	0.24	T;.
Sift4G	Benign	0.34	T;.
Polyphen		0.0020	B;.
Vest4		0.18
MutPred		0.45		Loss of solvent accessibility (P = 0.0155);.;
MVP		0.42
MPC		0.27
ClinPred		0.16	T
GERP RS		1.6
Varity_R		0.050
gMVP		0.37
Mutation Taster		=95/5	polymorphism

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: rs147632811; hg19: chr16-74773946;