rs929881

chr16-74774527-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_024306.5(FA2H):c.229C>T(p.Leu77=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.305 in 1,544,230 control chromosomes in the GnomAD database, including 75,258 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.32 (8553 hom., cov: 32)
  • Exomes 𝑓: 0.30 (66705 hom.)
• Consequence: FA2H NM_024306.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 2.61

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 Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.5).
• BP6: Variant 16-74774527-G-A is Benign according to our data. Variant chr16-74774527-G-A is described in ClinVar as [Benign]. Clinvar id is 129028.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-74774527-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=2.61 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.426 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FA2H	NM_024306.5	c.229C>T	p.Leu77=	synonymous_variant	1/7	ENST00000219368.8
FA2H	XM_011523317.4	c.229C>T	p.Leu77=	synonymous_variant	1/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FA2H	ENST00000219368.8	c.229C>T	p.Leu77=	synonymous_variant	1/7	1	NM_024306.5	P1
FA2H	ENST00000567683.5	c.229C>T	p.Leu77=	synonymous_variant, NMD_transcript_variant	1/5	2

Frequencies

GnomAD3 genomes AF: 0.323 AC: 49093 AN: 151984 Hom.: 8543 Cov.: 32

Gnomad AFR AF: 0.431

Gnomad AMI AF: 0.279

Gnomad AMR AF: 0.251

Gnomad ASJ AF: 0.370

Gnomad EAS AF: 0.0443

Gnomad SAS AF: 0.185

Gnomad FIN AF: 0.248

Gnomad MID AF: 0.342

Gnomad NFE AF: 0.314

Gnomad OTH AF: 0.331

GnomAD3 exomes AF: 0.276 AC: 45677 AN: 165328 Hom.: 7001 AF XY: 0.276 AC XY: 25629 AN XY: 92720

Gnomad AFR exome AF: 0.467

Gnomad AMR exome AF: 0.207

Gnomad ASJ exome AF: 0.398

Gnomad EAS exome AF: 0.0417

Gnomad SAS exome AF: 0.185

Gnomad FIN exome AF: 0.265

Gnomad NFE exome AF: 0.330

Gnomad OTH exome AF: 0.303

GnomAD4 exome AF: 0.303 AC: 421292 AN: 1392126 Hom.: 66705 Cov.: 34 AF XY: 0.299 AC XY: 206082 AN XY: 689134

Gnomad4 AFR exome AF: 0.455

Gnomad4 AMR exome AF: 0.211

Gnomad4 ASJ exome AF: 0.371

Gnomad4 EAS exome AF: 0.0442

Gnomad4 SAS exome AF: 0.176

Gnomad4 FIN exome AF: 0.253

Gnomad4 NFE exome AF: 0.319

Gnomad4 OTH exome AF: 0.301

GnomAD4 genome AF: 0.323 AC: 49137 AN: 152104 Hom.: 8553 Cov.: 32 AF XY: 0.316 AC XY: 23522 AN XY: 74368

Gnomad4 AFR AF: 0.431

Gnomad4 AMR AF: 0.251

Gnomad4 ASJ AF: 0.370

Gnomad4 EAS AF: 0.0442

Gnomad4 SAS AF: 0.184

Gnomad4 FIN AF: 0.248

Gnomad4 NFE AF: 0.314

Gnomad4 OTH AF: 0.331

Alfa AF: 0.316 Hom.: 8478

Bravo AF: 0.327

Asia WGS AF: 0.181 AC: 629 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 14, 2017	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 22, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 15, 2013	- -

Hereditary spastic paraplegia 35 Benign:4

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	Sep 21, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -

Spastic paraplegia Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Hereditary spastic paraplegia Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Dec 12, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
Cadd	Benign	13
Dann	Benign	0.94

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

Publications

LitVar

Other links and lift over

dbSNP: rs929881; hg19: chr16-74808425; COSMIC: COSV54725551;