chr16-74727349-A-G

Position:

• chr16-74727349-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_024306.5(FA2H):​c.401T>C​(p.Val134Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: FA2H NM_024306.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.05

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FA2H	NM_024306.5	c.401T>C	p.Val134Ala	missense_variant	3/7	ENST00000219368.8	NP_077282.3
FA2H	XM_011523317.4	c.401T>C	p.Val134Ala	missense_variant	3/6		XP_011521619.1
FA2H	XM_011523319.3	c.161T>C	p.Val54Ala	missense_variant	3/7		XP_011521621.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FA2H	ENST00000219368.8	c.401T>C	p.Val134Ala	missense_variant	3/7	1	NM_024306.5	ENSP00000219368	P1
FA2H	ENST00000569949.1	c.203T>C	p.Val68Ala	missense_variant	3/5	4		ENSP00000464576
FA2H	ENST00000567683.5	c.364-8189T>C		intron_variant, NMD_transcript_variant		2		ENSP00000455126

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.51
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.19
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.60	D;T
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.86	D;D
M_CAP	Pathogenic	0.38	D
MetaRNN	Uncertain	0.71	D;D
MetaSVM	Uncertain	0.66	D
MutationAssessor	Pathogenic	3.6	H;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.36	T
PROVEAN	Uncertain	-3.4	D;.
REVEL	Pathogenic	0.79
Sift	Benign	0.13	T;.
Sift4G	Benign	0.080	T;.
Polyphen		0.93	P;.
Vest4		0.95
MutPred		0.51		Gain of catalytic residue at V134 (P = 0.1177);.;
MVP		0.79
MPC		0.82
ClinPred		0.99	D
GERP RS		4.5
Varity_R		0.32
gMVP		0.77

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs199659429; hg19: chr16-74761247;