16-74727307-G-A

Position:

• chr16-74727307-G-A

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_Very_Strong

The ENST00000219368.8(FA2H):​c.443C>T​(p.Pro148Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000274 in 1,461,758 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P148T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000027 (0 hom.)
• Consequence: FA2H ENST00000219368.8 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 9.70

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]

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.967
• PP5: Variant 16-74727307-G-A is Pathogenic according to our data. Variant chr16-74727307-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 406877.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FA2H	NM_024306.5	c.443C>T	p.Pro148Leu	missense_variant	3/7	ENST00000219368.8	NP_077282.3
FA2H	XM_011523317.4	c.443C>T	p.Pro148Leu	missense_variant	3/6		XP_011521619.1
FA2H	XM_011523319.3	c.203C>T	p.Pro68Leu	missense_variant	3/7		XP_011521621.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FA2H	ENST00000219368.8	c.443C>T	p.Pro148Leu	missense_variant	3/7	1	NM_024306.5	ENSP00000219368.3
FA2H	ENST00000569949.1	c.245C>T	p.Pro82Leu	missense_variant	3/5	4		ENSP00000464576.1
FA2H	ENST00000567683.5	n.364-8147C>T		intron_variant		2		ENSP00000455126.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251024 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135778

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 SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000274 AC: 40 AN: 1461758 Hom.: 0 Cov.: 32 AF XY: 0.0000289 AC XY: 21 AN XY: 727182

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000324

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome Cov.: 33

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Spastic paraplegia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 16, 2023

Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt FA2H protein function. This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 148 of the FA2H protein (p.Pro148Leu). This variant is present in population databases (rs372350326, gnomAD 0.003%). This missense change has been observed in individual(s) with autosomal recessive hereditary spastic paraplegia (PMID: 29980238; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 406877). For these reasons, this variant has been classified as Pathogenic. -

Neurodegeneration with brain iron accumulation Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Mar 08, 2024

Variant summary: FA2H c.443C>T (p.Pro148Leu) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251024 control chromosomes. c.443C>T has been reported in the literature in at-least four individuals affected with early onset cerebellar ataxia, multifocal childhood onset dystonia and AR Hereditary spastic paraplegias (example, Shakya _2019, Powis_2020, Dong_2018). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 29980238, 31628766, 31429931). ClinVar contains an entry for this variant (Variation ID: 406877). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Inborn genetic diseases Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 12, 2016

- -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Mayo Clinic Laboratories, Mayo Clinic

Nov 19, 2021

PP3, PM2, PM3, PS4_moderate -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.68
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.83	D;D
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.97
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.93	D;D
M_CAP	Pathogenic	0.78	D
MetaRNN	Pathogenic	0.97	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.8	H;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.71	T
PROVEAN	Pathogenic	-10	D;.
REVEL	Pathogenic	0.95
Sift	Pathogenic	0.0	D;.
Sift4G	Pathogenic	0.0	D;.
Polyphen		1.0	D;.
Vest4		0.97
MVP		0.98
MPC		0.83
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.90
gMVP		0.87

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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

Other links and lift over

dbSNP: rs372350326; hg19: chr16-74761205; COSMIC: COSV99548031; COSMIC: COSV99548031;