16-74727349-A-G

Variant names:

• chr16-74727349-A-G
• rs199659429
• NM_024306.5:c.401T>C

Variant summary

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

The ENST00000219368.8(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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V134L) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: FA2H ENST00000219368.8 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.05
• Publications: 5 publications found

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]

FA2H Gene-Disease associations (from GenCC):

• hereditary spastic paraplegia 35

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae), G2P

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000219368.8. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FA2H	NM_024306.5	MANE Select	c.401T>C	p.Val134Ala	missense	Exon 3 of 7	NP_077282.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FA2H	ENST00000219368.8	TSL:1 MANE Select	c.401T>C	p.Val134Ala	missense	Exon 3 of 7	ENSP00000219368.3
	FA2H	ENST00000569949.1	TSL:4	c.203T>C	p.Val68Ala	missense	Exon 3 of 5	ENSP00000464576.1
	FA2H	ENST00000567683.5	TSL:2	n.364-8189T>C		intron	N/A	ENSP00000455126.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

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
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.86	D
M_CAP	Pathogenic	0.38	D
MetaRNN	Uncertain	0.71	D
MetaSVM	Uncertain	0.66	D
MutationAssessor	Pathogenic	3.6	H
PhyloP100		9.1
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

Other links and lift over

dbSNP: rs199659429; hg19: chr16-74761247;