rs759947457

Variant names:

• chr16-74774579-GCTGATGTCCTGGCCCGCC-G
• rs759947457
• NM_024306.5:c.159_176delGGCGGGCCAGGACATCAG

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PM1 PM4 PP5_Very_Strong

The NM_024306.5(FA2H):​c.159_176delGGCGGGCCAGGACATCAG​(p.Arg53_Ile58del) variant causes a disruptive inframe deletion change. The variant allele was found at a frequency of 0.00000793 in 1,386,604 control chromosomes in the GnomAD database, with no homozygous occurrence. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. R53R) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000079 (0 hom.)
• Consequence: FA2H NM_024306.5 disruptive_inframe_deletion
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 6.98
• Publications: 2 publications found

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

ACMG classification

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

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_024306.5
• PM4: Nonframeshift variant in NON repetitive region in NM_024306.5.
• PP5: Variant 16-74774579-GCTGATGTCCTGGCCCGCC-G is Pathogenic according to our data. Variant chr16-74774579-GCTGATGTCCTGGCCCGCC-G is described in ClinVar as Pathogenic. ClinVar VariationId is 30871.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FA2H	NM_024306.5	c.159_176delGGCGGGCCAGGACATCAG	p.Arg53_Ile58del	disruptive_inframe_deletion	Exon 1 of 7	ENST00000219368.8	NP_077282.3
FA2H	XM_011523317.4	c.159_176delGGCGGGCCAGGACATCAG	p.Arg53_Ile58del	disruptive_inframe_deletion	Exon 1 of 6		XP_011521619.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FA2H	ENST00000219368.8	c.159_176delGGCGGGCCAGGACATCAG	p.Arg53_Ile58del	disruptive_inframe_deletion	Exon 1 of 7	1	NM_024306.5	ENSP00000219368.3
FA2H	ENST00000567683.5	n.159_176delGGCGGGCCAGGACATCAG		non_coding_transcript_exon_variant	Exon 1 of 5	2		ENSP00000455126.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000221 AC: 3 AN: 135670 AF XY: 0.0000395

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS 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: 0.00000793 AC: 11 AN: 1386604 Hom.: 0 AF XY: 0.0000146 AC XY: 10 AN XY: 686366

African (AFR) AF: 0.00 AC: 0 AN: 30076

American (AMR) AF: 0.00 AC: 0 AN: 36960

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24530

East Asian (EAS) AF: 0.00 AC: 0 AN: 33978

South Asian (SAS) AF: 0.000141 AC: 11 AN: 77966

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 35842

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5038

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1084336

Other (OTH) AF: 0.00 AC: 0 AN: 57878

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary spastic paraplegia 35 Pathogenic:4

-

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.002%). Inframe deletion located in a nonrepeat region is predicted to change the length of the protein and disrupt normal protein function. Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 20104589). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (PMID: 31130284, 33246395). The variant has been reported to co-segregate with the disease in at least one similarly affected relative/individual in the the same family or the similarly affected unrelated family (PMID: 31130284, 33246395). The variant has been reported to be associated with FA2H-related disorder (ClinVar ID: VCV000030871 / PMID: 20104589). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -

May 20, 2023

Neuberg Centre For Genomic Medicine, NCGM

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The observed inframe deletion c.159_176del(p.Arg53_Ile58del) variant has been reported previously in homozygous state in patients affected with spastic paraplegia (Abbas S, et. al., 2021). Functional studies demonstrate a damaging effect suggesting loss of function (Dick et al., 2010). This variant is present with an allele frequency of 0.002% in gnomAD Exomes database. This variant has been reported to the ClinVar database as Pathogenic (multiple submissions). It has also been observed to segregate with disease in related individuals (Abbas S, et. al., 2021). This p.Arg53_Ile58del causes deletion of amino acid Arginine at position 53 to Isoleucine at position 58. For these reasons, this variant has been classified as Pathogenic. -

Nov 02, 2023

Department of Biotechnology and Genetic Engineering, Kohat University of Science and Technology

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Apr 01, 2010

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Spastic paraplegia Pathogenic:1

Oct 24, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant, c.159_176del, results in the deletion of 6 amino acid(s) of the FA2H protein (p.Arg53_Ile58del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs759947457, gnomAD 0.01%). This variant has been observed in individuals with clinical features of FA2H-related conditions and/or hereditary spastic paraplegia (PMID: 20104589, 31130284, 33246395; internal data). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 30871). Algorithms developed to predict the effect of variants on gene product structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects FA2H function (PMID: 20104589). For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:1

Jan 22, 2025

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate a damaging effect suggesting loss of function (PMID: 20104589); In-frame deletion of 6 amino acids in a non-repeat region; In silico analysis supports a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 31130284, 37152446, 20104589, 33246395, 24359114, 38275596, 36109173, 38306901, 36002593, 37510308, 39304850) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.0
Mutation Taster		=5/195	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs759947457; hg19: chr16-74808477;