Genetic Variant NM_024306.5:c.43G>A (chr16-74774713-C-T) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PP3_Moderate

The NM_024306.5(FA2H):c.43G>A(p.Glu15Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000000835 in 1,197,732 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. E15E) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 8.3e-7 ( 0 hom. )

Consequence

FA2H
NM_024306.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.48

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM1

In a domain Cytochrome b5 heme-binding (size 78) in uniprot entity FA2H_HUMAN there are 10 pathogenic changes around while only 2 benign (83%) in NM_024306.5

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.869

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FA2H	NM_024306.5 link	c.43G>A	p.Glu15Lys	missense_variant	Exon 1 of 7	ENST00000219368.8	NP_077282.3	Q7L5A8-1
FA2H	XM_011523317.4 link	c.43G>A	p.Glu15Lys	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.43G>A	p.Glu15Lys	missense_variant	Exon 1 of 7	1	NM_024306.5	ENSP00000219368.3		Q7L5A8-1
FA2H	ENST00000567683.5 link	n.43G>A		non_coding_transcript_exon_variant	Exon 1 of 5	2		ENSP00000455126.1		H3BP32

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

8.35e-7

AC:

AN:

1197732

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

583112

show subpopulations

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:

0.00000101

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jun 28, 2017

Athena Diagnostics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.59

BayesDel_addAF

Pathogenic

0.24

BayesDel_noAF

Uncertain

0.11

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.56

Eigen

Pathogenic

0.79

Eigen_PC

Uncertain

0.66

FATHMM_MKL

Uncertain

0.88

LIST_S2

Benign

0.64

M_CAP

Pathogenic

0.99

MetaRNN

Pathogenic

0.87

MetaSVM

Pathogenic

0.87

MutationAssessor

Pathogenic

4.1

PrimateAI

Pathogenic

0.96

PROVEAN

Benign

-1.5

REVEL

Pathogenic

0.75

Sift

Uncertain

0.010

Sift4G

Uncertain

0.019

Polyphen

1.0

Vest4

0.54

MutPred

0.78

Gain of catalytic residue at E15 (P = 0.0067);

MVP

0.56

MPC

3.0

ClinPred

1.0

GERP RS

4.0

Varity_R

0.85

gMVP

0.91

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over