rs141854925

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_StrongBS1_Supporting

The NM_024306.5(FA2H):c.1112C>T(p.Thr371Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000189 in 1,560,598 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. T371T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00015 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00019 ( 0 hom. )

Consequence

FA2H
NM_024306.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:1

Conservation

PhyloP100: 0.0940

Publications

5 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: Likely_benign. The variant received -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.011379689).

BS1

Variant frequency is greater than expected in population sas. GnomAdExome4 allele frequency = 0.000193 (272/1408390) while in subpopulation SAS AF = 0.000764 (61/79874). AF 95% confidence interval is 0.00061. There are 0 homozygotes in GnomAdExome4. There are 153 alleles in the male GnomAdExome4 subpopulation. Median coverage is 30. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FA2H	NM_024306.5	MANE Select	c.1112C>T	p.Thr371Met	missense	Exon 7 of 7	NP_077282.3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
FA2H	ENST00000219368.8	TSL:1 MANE Select	c.1112C>T	p.Thr371Met	missense	Exon 7 of 7	ENSP00000219368.3
FA2H	ENST00000562145.1	TSL:1	n.833C>T		non_coding_transcript_exon	Exon 2 of 2
FA2H	ENST00000567683.5	TSL:2	n.*391C>T		non_coding_transcript_exon	Exon 5 of 5	ENSP00000455126.1

Frequencies

GnomAD3 genomes

AF:

0.000151

AC:

AN:

152208

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00115

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.0000942

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000191

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000286

AC:

AN:

171506

AF XY:

0.000352

show subpopulations

Gnomad AFR exome

AF:

0.000101

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.000801

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000620

Gnomad NFE exome

AF:

0.000288

Gnomad OTH exome

AF:

0.000629

GnomAD4 exome

AF:

0.000193

AC:

272

AN:

1408390

Hom.:

Cov.:

AF XY:

0.000220

AC XY:

153

AN XY:

695796

show subpopulations

African (AFR)

AF:

0.0000312

AC:

AN:

32040

American (AMR)

AF:

0.00

AC:

AN:

37024

Ashkenazi Jewish (ASJ)

AF:

0.000555

AC:

AN:

25246

East Asian (EAS)

AF:

0.0000273

AC:

AN:

36604

South Asian (SAS)

AF:

0.000764

AC:

AN:

79874

European-Finnish (FIN)

AF:

0.0000798

AC:

AN:

50120

Middle Eastern (MID)

AF:

0.000177

AC:

AN:

5652

European-Non Finnish (NFE)

AF:

0.000161

AC:

174

AN:

1083372

Other (OTH)

AF:

0.000274

AC:

AN:

58458

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

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:

0.000151

AC:

AN:

152208

Hom.:

Cov.:

AF XY:

0.000134

AC XY:

AN XY:

74358

show subpopulations

African (AFR)

AF:

0.0000724

AC:

AN:

41452

American (AMR)

AF:

0.00

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00115

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.000207

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.0000942

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000191

AC:

AN:

68040

Other (OTH)

AF:

0.000478

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

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:

0.000307

Hom.:

Bravo

AF:

0.000185

ESP6500AA

AF:

0.000228

AC:

ESP6500EA

AF:

0.000700

AC:

ExAC

AF:

0.000196

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Hereditary spastic paraplegia (1)

Hereditary spastic paraplegia 35 (1)

Spastic paraplegia (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.061

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.43

CADD

Benign

7.8

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.12

Eigen

Benign

-0.94

Eigen_PC

Benign

-0.92

FATHMM_MKL

Benign

0.045

LIST_S2

Benign

0.54

M_CAP

Benign

0.037

MetaRNN

Benign

0.011

MetaSVM

Benign

-0.79

MutationAssessor

Benign

0.57

PhyloP100

0.094

PrimateAI

Benign

0.29

PROVEAN

Benign

-0.11

REVEL

Benign

0.12

Sift

Benign

0.46

Sift4G

Benign

0.29

Polyphen

0.079

Vest4

0.055

MVP

0.19

MPC

0.23

ClinPred

0.0073

GERP RS

-0.41

Varity_R

0.012

gMVP

0.55

Mutation Taster

=98/2

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

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over