Genetic Variant NM_024306.5:c.94C>T (chr16-74774662-G-A) – ACMG Classification: Uncertain_significance (5 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM1PM2PP3

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

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.56

Publications

0 publications found

Variant links:

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

FA2H links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 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 rank	MANE	Protein	UniProt
FA2H	NM_024306.5 link	c.94C>T	p.Arg32Cys	missense_variant	Exon 1 of 7	ENST00000219368.8	NP_077282.3	Q7L5A8-1
FA2H	XM_011523317.4 link	c.94C>T	p.Arg32Cys	missense_variant	Exon 1 of 6		XP_011521619.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FA2H	ENST00000219368.8 link	c.94C>T	p.Arg32Cys	missense_variant	Exon 1 of 7	1	NM_024306.5	ENSP00000219368.3		Q7L5A8-1
FA2H	ENST00000567683.5 link	n.94C>T		non_coding_transcript_exon_variant	Exon 1 of 5	2		ENSP00000455126.1		H3BP32

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.78e-7

AC:

AN:

1285852

Hom.:

Cov.:

AF XY:

0.00000158

AC XY:

AN XY:

632382

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26388

American (AMR)

AF:

0.00

AC:

AN:

23610

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

22352

East Asian (EAS)

AF:

0.00

AC:

AN:

27860

South Asian (SAS)

AF:

0.00

AC:

AN:

65334

European-Finnish (FIN)

AF:

0.00

AC:

AN:

32414

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3864

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1030846

Other (OTH)

AF:

0.0000188

AC:

AN:

53184

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

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

BayesDel_noAF

Benign

-0.090

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.71

Eigen

Uncertain

0.22

Eigen_PC

Benign

0.13

FATHMM_MKL

Benign

0.60

LIST_S2

Benign

0.84

M_CAP

Pathogenic

0.99

MetaRNN

Pathogenic

0.80

MetaSVM

Uncertain

-0.21

MutationAssessor

Uncertain

2.6

PhyloP100

1.6

PrimateAI

Pathogenic

0.95

PROVEAN

Uncertain

-3.8

REVEL

Uncertain

0.58

Sift

Uncertain

0.0050

Sift4G

Uncertain

0.021

Polyphen

1.0

Vest4

0.52

MutPred

0.60

Loss of MoRF binding (P = 0.0054);

MVP

0.36

MPC

3.3

ClinPred

0.99

GERP RS

1.9

PromoterAI

0.15

Neutral

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over