16-74774754-A-G

Variant names:

• chr16-74774754-A-G
• rs1555542889
• NM_024306.5:c.2T>C

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PVS1 PS1_Moderate PM2 PP5_Moderate

The NM_024306.5(FA2H):​c.2T>C​(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000868 in 1,152,396 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 8.7e-7 (0 hom.)
• Consequence: FA2H NM_024306.5 start_lost
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 2.32
• Publications: 0 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 14 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 25 pathogenic variants. Next in-frame start position is after 93 codons. Genomic position: 74740109. Lost 0.248 part of the original CDS.
• PS1: Another start lost variant in NM_024306.5 (FA2H) was described as [Pathogenic] in ClinVar
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 16-74774754-A-G is Pathogenic according to our data. Variant chr16-74774754-A-G is described in ClinVar as Pathogenic. ClinVar VariationId is 458306.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	c.2T>C	p.Met1?	start_lost	Exon 1 of 7	ENST00000219368.8	NP_077282.3
FA2H	XM_011523317.4	c.2T>C	p.Met1?	start_lost	Exon 1 of 6		XP_011521619.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FA2H	ENST00000219368.8	c.2T>C	p.Met1?	start_lost	Exon 1 of 7	1	NM_024306.5	ENSP00000219368.3
FA2H	ENST00000567683.5	n.2T>C		non_coding_transcript_exon_variant	Exon 1 of 5	2		ENSP00000455126.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 8.68e-7 AC: 1 AN: 1152396 Hom.: 0 Cov.: 33 AF XY: 0.00000180 AC XY: 1 AN XY: 554914

African (AFR) AF: 0.00 AC: 0 AN: 23042

American (AMR) AF: 0.00 AC: 0 AN: 8420

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15220

East Asian (EAS) AF: 0.00 AC: 0 AN: 26286

South Asian (SAS) AF: 0.00 AC: 0 AN: 36884

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 26012

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3150

European-Non Finnish (NFE) AF: 0.00000103 AC: 1 AN: 966580

Other (OTH) AF: 0.00 AC: 0 AN: 46802

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Spastic paraplegia Pathogenic:1

Jun 04, 2021

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. This variant disrupts the initiator methionine in FA2H. If translation initiates from the next-in-frame methionine, the FA2H protein would no longer include the region containing p.Glu78 amino acid residue. Other variant(s) that disrupt this residue have been observed in individuals with FA2H-related conditions (PMID: 31135052, 31429931). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. This variant has been observed in individual(s) with clinical features of hereditary spastic paraplegia (Invitae). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the ExAC database. This sequence change affects the initiator methionine of the FA2H mRNA. The next in-frame methionine is located at codon 93. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.25
CADD	Uncertain	24
DANN	Benign	0.97
DEOGEN2	Benign	0.15	T
Eigen	Benign	-0.11
Eigen_PC	Benign	-0.0056
FATHMM_MKL	Benign	0.38	N
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	1.0	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Uncertain	-0.21	T
PhyloP100		2.3
PROVEAN	Benign	-0.69	N
REVEL	Uncertain	0.56
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.14	B
Vest4		0.60
MutPred		0.96		Gain of glycosylation at M1 (P = 9e-04);
MVP		0.53
ClinPred		0.98	D
GERP RS		4.0
PromoterAI		-0.15	Neutral
Varity_R		0.83
gMVP		0.68
Mutation Taster		=12/188	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs1555542889; hg19: chr16-74808652;