dbSNP rs1555542889: FA2H:p.Met1? (chr16-74774754-A-C) – ACMG Classification: Pathogenic (12 pts)

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1PS1_ModeratePM2

The NM_024306.5(FA2H):c.2T>G(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000868 in 1,152,398 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.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 8.7e-7 ( 0 hom. )

Consequence

FA2H
NM_024306.5 start_lost

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.32

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 12 ACMG points.

PVS1

Start lost variant, next in-frame start position is after 25 pathogenic variants. Next in-frame start position is after 93 codons. Genomic position: 74740109. Lost 0.248 part of the original CDS.

PS1

Another start lost variant in NM_024306.5 (FA2H) was described as [Pathogenic] in ClinVar

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FA2H	NM_024306.5 link	c.2T>G	p.Met1?	start_lost	Exon 1 of 7	ENST00000219368.8	NP_077282.3	Q7L5A8-1
FA2H	XM_011523317.4 link	c.2T>G	p.Met1?	start_lost	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.2T>G	p.Met1?	start_lost	Exon 1 of 7	1	NM_024306.5	ENSP00000219368.3		Q7L5A8-1
FA2H	ENST00000567683.5 link	n.2T>G		non_coding_transcript_exon_variant	Exon 1 of 5	2		ENSP00000455126.1		H3BP32

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

8.68e-7

AC:

AN:

1152398

Hom.:

Cov.:

AF XY:

0.00000180

AC XY:

AN XY:

554916

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

23042

American (AMR)

AF:

0.00

AC:

AN:

8420

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

15220

East Asian (EAS)

AF:

0.00

AC:

AN:

26286

South Asian (SAS)

AF:

0.0000271

AC:

AN:

36884

European-Finnish (FIN)

AF:

0.00

AC:

AN:

26012

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3150

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

966582

Other (OTH)

AF:

0.00

AC:

AN:

46802

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

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.63

BayesDel_noAF

Pathogenic

0.29

CADD

Uncertain

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.16

Eigen

Uncertain

0.31

Eigen_PC

Uncertain

0.29

FATHMM_MKL

Benign

0.44

LIST_S2

Uncertain

0.90

M_CAP

Pathogenic

1.0

MetaRNN

Pathogenic

0.98

MetaSVM

Uncertain

0.25

PhyloP100

2.3

PROVEAN

Benign

-0.81

REVEL

Pathogenic

0.66

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

0.97

Vest4

0.55

MutPred

0.95

Gain of methylation at M1 (P = 0.0191);

MVP

0.61

ClinPred

0.98

GERP RS

4.0

PromoterAI

-0.17

Neutral

(source)

Varity_R

0.95

gMVP

0.81

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over