dbSNP rs878855083: FA2H:p.Pro274ArgfsTer38 (chr16-74716563-CAG-C) – ACMG Classification: Likely_pathogenic (8 pts)

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_StrongPM2PP5_Moderate

The NM_024306.5(FA2H):c.821_822delCT(p.Pro274ArgfsTer38) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,446,280 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★).

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

FA2H
NM_024306.5 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 9.95

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 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.266 CDS is truncated, and there are 0 pathogenic variants in the truncated region.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 16-74716563-CAG-C is Pathogenic according to our data. Variant chr16-74716563-CAG-C is described in ClinVar as [Pathogenic]. Clinvar id is 241466.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FA2H	NM_024306.5 link	c.821_822delCT	p.Pro274ArgfsTer38	frameshift_variant	Exon 6 of 7	ENST00000219368.8	NP_077282.3	Q7L5A8-1
FA2H	XM_011523319.3 link	c.581_582delCT	p.Pro194ArgfsTer38	frameshift_variant	Exon 6 of 7		XP_011521621.1
FA2H	XM_011523317.4 link	c.1685_1686delCT		3_prime_UTR_variant	Exon 6 of 6		XP_011521619.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
FA2H	ENST00000219368.8 link	c.821_822delCT	p.Pro274ArgfsTer38	frameshift_variant	Exon 6 of 7	1	NM_024306.5	ENSP00000219368.3	Q7L5A8-1
FA2H	ENST00000562145.1 link	n.542_543delCT		non_coding_transcript_exon_variant	Exon 1 of 2	1
FA2H	ENST00000567683.5 link	n.100_101delCT		non_coding_transcript_exon_variant	Exon 4 of 5	2		ENSP00000455126.1	H3BP32
FA2H	ENST00000567683.5 link	n.100_101delCT		3_prime_UTR_variant	Exon 4 of 5	2		ENSP00000455126.1	H3BP32

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000469

AC:

AN:

213276

Hom.:

AF XY:

0.00

AC XY:

AN XY:

115528

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000328

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000138

AC:

AN:

1446280

Hom.:

AF XY:

0.00000139

AC XY:

AN XY:

718178

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000240

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000167

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Spastic paraplegia

Pathogenic:1

Jun 15, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 241466). This variant has not been reported in the literature in individuals affected with FA2H-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.003%). This sequence change creates a premature translational stop signal (p.Pro274Argfs*38) in the FA2H gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in FA2H are known to be pathogenic (PMID: 20853438, 25496456, 25732363, 26344562). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over