rs35874850

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_024306.5(FA2H):c.289C>G(p.Pro97Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00852 in 1,613,458 control chromosomes in the GnomAD database, including 166 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.019 ( 65 hom., cov: 31)

Exomes 𝑓: 0.0074 ( 101 hom. )

Consequence

FA2H
NM_024306.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: -0.690

Publications

11 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: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0018601716).

BP6

Variant 16-74740097-G-C is Benign according to our data. Variant chr16-74740097-G-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 129029.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAdExome4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.053 is higher than 0.05.

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.289C>G	p.Pro97Ala	missense	Exon 2 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.289C>G	p.Pro97Ala	missense	Exon 2 of 7	ENSP00000219368.3	Q7L5A8-1
FA2H	ENST00000888352.1		c.289C>G	p.Pro97Ala	missense	Exon 2 of 7	ENSP00000558411.1
FA2H	ENST00000888351.1		c.289C>G	p.Pro97Ala	missense	Exon 2 of 7	ENSP00000558410.1

Frequencies

GnomAD3 genomes

AF:

0.0194

AC:

2950

AN:

152100

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0506

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00896

Gnomad ASJ

AF:

0.00461

Gnomad EAS

AF:

0.000386

Gnomad SAS

AF:

0.00456

Gnomad FIN

AF:

0.00273

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.00897

Gnomad OTH

AF:

0.0177

GnomAD2 exomes

AF:

0.00954

AC:

2399

AN:

251494

AF XY:

0.00858

show subpopulations

Gnomad AFR exome

AF:

0.0550

Gnomad AMR exome

AF:

0.00702

Gnomad ASJ exome

AF:

0.00327

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00554

Gnomad NFE exome

AF:

0.00820

Gnomad OTH exome

AF:

0.00717

GnomAD4 exome

AF:

0.00739

AC:

10792

AN:

1461240

Hom.:

101

Cov.:

AF XY:

0.00723

AC XY:

5257

AN XY:

726976

show subpopulations

African (AFR)

AF:

0.0551

AC:

1841

AN:

33440

American (AMR)

AF:

0.00780

AC:

349

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00337

AC:

AN:

26132

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39698

South Asian (SAS)

AF:

0.00434

AC:

374

AN:

86246

European-Finnish (FIN)

AF:

0.00485

AC:

259

AN:

53408

Middle Eastern (MID)

AF:

0.0149

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00648

AC:

7205

AN:

1111466

Other (OTH)

AF:

0.00974

AC:

588

AN:

60358

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.456

Heterozygous variant carriers

555

1110

1664

2219

2774

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

260

520

780

1040

1300

<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:

0.0194

AC:

2958

AN:

152218

Hom.:

Cov.:

AF XY:

0.0183

AC XY:

1364

AN XY:

74438

show subpopulations

African (AFR)

AF:

0.0506

AC:

2100

AN:

41512

American (AMR)

AF:

0.00895

AC:

137

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00461

AC:

AN:

3472

East Asian (EAS)

AF:

0.000387

AC:

AN:

5168

South Asian (SAS)

AF:

0.00436

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00273

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.0136

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00898

AC:

611

AN:

68012

Other (OTH)

AF:

0.0180

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

149

298

446

595

744

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

128

160

<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:

0.00758

Hom.:

Bravo

AF:

0.0215

TwinsUK

AF:

0.00512

AC:

ALSPAC

AF:

0.00597

AC:

ESP6500AA

AF:

0.0573

AC:

252

ESP6500EA

AF:

0.00756

AC:

ExAC

AF:

0.0109

AC:

1322

Asia WGS

AF:

0.0210

AC:

AN:

3478

EpiCase

AF:

0.0101

EpiControl

AF:

0.0100

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Hereditary spastic paraplegia 35 (3)

not specified (3)

Hereditary spastic paraplegia (1)

not provided (1)

Spastic paraplegia (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.046

BayesDel_addAF

Benign

-0.52

BayesDel_noAF

Benign

-0.48

CADD

Benign

0.20

(source)

DANN

Benign

0.55

DEOGEN2

Benign

0.089

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.0053

LIST_S2

Benign

0.21

MetaRNN

Benign

0.0019

MetaSVM

Benign

-0.98

MutationAssessor

Benign

-0.98

PhyloP100

-0.69

PrimateAI

Benign

0.30

PROVEAN

Benign

0.26

REVEL

Benign

0.17

Sift

Benign

0.79

Sift4G

Benign

0.83

Polyphen

0.0

Vest4

0.020

MPC

0.21

ClinPred

0.00014

GERP RS

-1.2

Varity_R

0.019

gMVP

0.19

Mutation Taster

=99/1

polymorphism (auto)

(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

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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