NM_024306.5:c.510_511delCA

Variant names:

• chr16-74726326-CTG-C
• rs587776891
• NM_024306.5:c.510_511delCA

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_024306.5(FA2H):​c.510_511delCA​(p.Tyr170fs) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: FA2H NM_024306.5 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 1.09
• Publications: 1 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 18 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 16-74726326-CTG-C is Pathogenic according to our data. Variant chr16-74726326-CTG-C is described in CliVar as Pathogenic. Clinvar id is 30873.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-74726326-CTG-C is described in CliVar as Pathogenic. Clinvar id is 30873.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-74726326-CTG-C is described in CliVar as Pathogenic. Clinvar id is 30873.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-74726326-CTG-C is described in CliVar as Pathogenic. Clinvar id is 30873.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-74726326-CTG-C is described in CliVar as Pathogenic. Clinvar id is 30873.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.510_511delCA	p.Tyr170fs	frameshift_variant	Exon 4 of 7	ENST00000219368.8	NP_077282.3
FA2H	XM_011523317.4	c.510_511delCA	p.Tyr170fs	frameshift_variant	Exon 4 of 6		XP_011521619.1
FA2H	XM_011523319.3	c.270_271delCA	p.Tyr90fs	frameshift_variant	Exon 4 of 7		XP_011521621.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FA2H	ENST00000219368.8	c.510_511delCA	p.Tyr170fs	frameshift_variant	Exon 4 of 7	1	NM_024306.5	ENSP00000219368.3
FA2H	ENST00000569949.1	c.312_313delCA	p.Tyr104fs	frameshift_variant	Exon 4 of 5	4		ENSP00000464576.1
FA2H	ENST00000567683.5	n.364-7168_364-7167delCA		intron_variant	Intron 2 of 4	2		ENSP00000455126.1
FA2H	ENST00000618933.1	c.-82_-81delCA		upstream_gene_variant		6		ENSP00000479548.1

Frequencies

GnomAD3 genomes Cov.: 33

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Jan 31, 2024

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP1, PM2, PM3, PVS1 -

Apr 08, 2025

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 23745665, 20853438, 31135052, 22965561, 29376581, 21592092, 23566484) -

Spastic paraplegia Pathogenic:1

Apr 09, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Tyr170*) 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). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 30873). This variant is also known as c.509_510delAC. This premature translational stop signal has been observed in individual(s) with clinical features of FA2H-related conditions (PMID: 20853438, 23745665, 31135052). This variant is not present in population databases (gnomAD no frequency). -

Hereditary spastic paraplegia 35 Pathogenic:1

Apr 01, 2014

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.1
Mutation Taster		=3/197	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs587776891; hg19: chr16-74760224;