chr16-74774579-GCTGATGTCCTGGCCCGCC-G

Variant names:

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

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PS3 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 (★★). ClinVar reports functional evidence for this variant: "SCV004013876: Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID:20104589)." and additional evidence is available in ClinVar. 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), ClinGen, G2P

ACMG classification

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV004013876: Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 20104589).; SCV005382297: Functional studies demonstrate a damaging effect suggesting loss of function (Dick et al., 2010).; SCV002586485: Published functional studies demonstrate a damaging effect suggesting loss of function (PMID: 20104589); SCV003260346: Experimental studies have shown that this variant affects FA2H function (PMID: 20104589).
• 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.

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.159_176delGGCGGGCCAGGACATCAG	p.Arg53_Ile58del	disruptive_inframe_deletion	Exon 1 of 7	NP_077282.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FA2H	ENST00000219368.8	TSL:1 MANE Select	c.159_176delGGCGGGCCAGGACATCAG	p.Arg53_Ile58del	disruptive_inframe_deletion	Exon 1 of 7	ENSP00000219368.3	Q7L5A8-1
	FA2H	ENST00000888352.1		c.159_176delGGCGGGCCAGGACATCAG	p.Arg53_Ile58del	disruptive_inframe_deletion	Exon 1 of 7	ENSP00000558411.1
	FA2H	ENST00000888351.1		c.159_176delGGCGGGCCAGGACATCAG	p.Arg53_Ile58del	disruptive_inframe_deletion	Exon 1 of 7	ENSP00000558410.1

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

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
4	-	-	Hereditary spastic paraplegia 35 (4)
1	-	-	not provided (1)
1	-	-	Spastic paraplegia (1)

Computational scores

Source: dbNSFP v4.9

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;