rs915291720

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PM1PM5PP3_StrongPP5_Very_Strong

The NM_024306.5(FA2H):c.131C>A(p.Pro44Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000594 in 1,516,080 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P44S) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000022 ( 0 hom. )

Consequence

FA2H
NM_024306.5 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:2

Conservation

PhyloP100: 6.79

Publications

2 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), ClinGen, G2P

FA2H links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 16 ACMG points.

PM1

In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_024306.5

PM5

Other missense variant is known to change same aminoacid residue: Variant chr16-74774626-G-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 449574.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.952

PP5

Variant 16-74774625-G-T is Pathogenic according to our data. Variant chr16-74774625-G-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 458305.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024306.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FA2H	NM_024306.5	MANE Select	c.131C>A	p.Pro44Gln	missense	Exon 1 of 7	NP_077282.3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FA2H	ENST00000219368.8	TSL:1 MANE Select	c.131C>A	p.Pro44Gln	missense	Exon 1 of 7	ENSP00000219368.3	Q7L5A8-1
FA2H	ENST00000888352.1		c.131C>A	p.Pro44Gln	missense	Exon 1 of 7	ENSP00000558411.1
FA2H	ENST00000888351.1		c.131C>A	p.Pro44Gln	missense	Exon 1 of 7	ENSP00000558410.1

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152144

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000327

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000220

AC:

AN:

1363828

Hom.:

Cov.:

AF XY:

0.00000148

AC XY:

AN XY:

673488

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

28828

American (AMR)

AF:

0.0000591

AC:

AN:

33826

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24306

East Asian (EAS)

AF:

0.00

AC:

AN:

32272

South Asian (SAS)

AF:

0.00

AC:

AN:

76386

European-Finnish (FIN)

AF:

0.00

AC:

AN:

34520

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4320

European-Non Finnish (NFE)

AF:

9.33e-7

AC:

AN:

1072360

Other (OTH)

AF:

0.00

AC:

AN:

57010

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

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

AF:

0.0000394

AC:

AN:

152252

Hom.:

Cov.:

AF XY:

0.0000537

AC XY:

AN XY:

74448

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41570

American (AMR)

AF:

0.000327

AC:

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5162

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67992

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.517

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000567

ClinVar

ClinVar submissions

Significance:Pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Neurodegeneration with brain iron accumulation (1)

Spastic paraplegia (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.88

BayesDel_addAF

Pathogenic

0.50

BayesDel_noAF

Pathogenic

0.49

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.89

Eigen

Pathogenic

0.82

Eigen_PC

Pathogenic

0.71

FATHMM_MKL

Uncertain

0.81

LIST_S2

Benign

0.86

M_CAP

Pathogenic

0.99

MetaRNN

Pathogenic

0.95

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.8

PhyloP100

6.8

PrimateAI

Pathogenic

0.89

PROVEAN

Pathogenic

-6.5

REVEL

Pathogenic

0.92

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.90

MutPred

0.70

Gain of MoRF binding (P = 0.0328)

MVP

0.75

MPC

2.8

ClinPred

1.0

GERP RS

4.1

PromoterAI

-0.0086

Neutral

(source)

Varity_R

0.96

gMVP

0.86

Mutation Taster

=165/135

polymorphism

(source)

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over