Genetic Variant FA2H:p.Asp57GlyfsTer48 (chr16-74774586-T-TCCTGGCCCGC) – ACMG Classification: Pathogenic (12 pts)

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate

The NM_024306.5(FA2H):c.160_169dupGCGGGCCAGG(p.Asp57GlyfsTer48) variant causes a frameshift change. The variant allele was found at a frequency of 0.0000013 in 1,534,250 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 7.2e-7 ( 0 hom. )

Consequence

FA2H
NM_024306.5 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 5.18

Publications

3 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:

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ACMG classification

Classification was made for transcript

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

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 16-74774586-T-TCCTGGCCCGC is Pathogenic according to our data. Variant chr16-74774586-T-TCCTGGCCCGC is described in ClinVar as Pathogenic. ClinVar VariationId is 242580.Status of the report is criteria_provided_single_submitter, 1 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.160_169dupGCGGGCCAGG	p.Asp57GlyfsTer48	frameshift	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.160_169dupGCGGGCCAGG	p.Asp57GlyfsTer48	frameshift	Exon 1 of 7	ENSP00000219368.3	Q7L5A8-1
FA2H	ENST00000888352.1		c.160_169dupGCGGGCCAGG	p.Asp57GlyfsTer48	frameshift	Exon 1 of 7	ENSP00000558411.1
FA2H	ENST00000888351.1		c.160_169dupGCGGGCCAGG	p.Asp57GlyfsTer48	frameshift	Exon 1 of 7	ENSP00000558410.1

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

152090

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

7.24e-7

AC:

AN:

1382160

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

683850

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

29800

American (AMR)

AF:

0.0000275

AC:

AN:

36308

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24506

East Asian (EAS)

AF:

0.00

AC:

AN:

33582

South Asian (SAS)

AF:

0.00

AC:

AN:

77696

European-Finnish (FIN)

AF:

0.00

AC:

AN:

35548

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4916

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1082060

Other (OTH)

AF:

0.00

AC:

AN:

57744

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

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:

0.00000658

AC:

AN:

152090

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74292

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41430

American (AMR)

AF:

0.00

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5172

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10608

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67974

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

ClinVar

ClinVar submissions

Significance:Pathogenic

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Spastic paraplegia (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

5.2

Mutation Taster

=114/186

disease causing

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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16-74774586-TCCTGGCCCGC-TCCTGGCCCGCCCTGGCCCGC

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over