rs11554621

chr16-74716498-T-C

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.888A>G(p.Val296=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.145 in 1,613,310 control chromosomes in the GnomAD database, including 18,651 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.15 (2000 hom., cov: 30)
  • Exomes 𝑓: 0.14 (16651 hom.)
• Consequence: FA2H NM_024306.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 1.30

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=-0.65).
• BP6: Variant 16-74716498-T-C is Benign according to our data. Variant chr16-74716498-T-C is described in ClinVar as [Benign]. Clinvar id is 129032.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-74716498-T-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=1.3 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.217 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FA2H	NM_024306.5	c.888A>G	p.Val296=	synonymous_variant	6/7	ENST00000219368.8
FA2H	XM_011523319.3	c.648A>G	p.Val216=	synonymous_variant	6/7
FA2H	XM_011523317.4	c.*1752A>G		3_prime_UTR_variant	6/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FA2H	ENST00000219368.8	c.888A>G	p.Val296=	synonymous_variant	6/7	1	NM_024306.5	P1
FA2H	ENST00000562145.1	n.609A>G		non_coding_transcript_exon_variant	1/2	1
FA2H	ENST00000567683.5	c.*167A>G		3_prime_UTR_variant, NMD_transcript_variant	4/5	2

Frequencies

GnomAD3 genomes AF: 0.153 AC: 23221 AN: 151608 Hom.: 1990 Cov.: 30

Gnomad AFR AF: 0.220

Gnomad AMI AF: 0.135

Gnomad AMR AF: 0.115

Gnomad ASJ AF: 0.105

Gnomad EAS AF: 0.0484

Gnomad SAS AF: 0.0668

Gnomad FIN AF: 0.0586

Gnomad MID AF: 0.0949

Gnomad NFE AF: 0.153

Gnomad OTH AF: 0.158

GnomAD3 exomes AF: 0.116 AC: 29064 AN: 250082 Hom.: 2037 AF XY: 0.115 AC XY: 15606 AN XY: 135236

Gnomad AFR exome AF: 0.217

Gnomad AMR exome AF: 0.0770

Gnomad ASJ exome AF: 0.104

Gnomad EAS exome AF: 0.0508

Gnomad SAS exome AF: 0.0592

Gnomad FIN exome AF: 0.0608

Gnomad NFE exome AF: 0.151

Gnomad OTH exome AF: 0.126

GnomAD4 exome AF: 0.145 AC: 211319 AN: 1461584 Hom.: 16651 Cov.: 31 AF XY: 0.142 AC XY: 103185 AN XY: 727086

Gnomad4 AFR exome AF: 0.222

Gnomad4 AMR exome AF: 0.0816

Gnomad4 ASJ exome AF: 0.104

Gnomad4 EAS exome AF: 0.0410

Gnomad4 SAS exome AF: 0.0607

Gnomad4 FIN exome AF: 0.0631

Gnomad4 NFE exome AF: 0.160

Gnomad4 OTH exome AF: 0.139

GnomAD4 genome AF: 0.153 AC: 23268 AN: 151726 Hom.: 2000 Cov.: 30 AF XY: 0.145 AC XY: 10779 AN XY: 74152

Gnomad4 AFR AF: 0.220

Gnomad4 AMR AF: 0.115

Gnomad4 ASJ AF: 0.105

Gnomad4 EAS AF: 0.0488

Gnomad4 SAS AF: 0.0666

Gnomad4 FIN AF: 0.0586

Gnomad4 NFE AF: 0.153

Gnomad4 OTH AF: 0.157

Alfa AF: 0.156 Hom.: 920

Bravo AF: 0.162

Asia WGS AF: 0.0900 AC: 313 AN: 3478

EpiCase AF: 0.157

EpiControl AF: 0.157

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 24, 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	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Hereditary spastic paraplegia 35 Benign:3

Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -
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. -

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	-0.65
Cadd	Benign	9.9
Dann	Benign	0.70

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: rs11554621; hg19: chr16-74750396; COSMIC: COSV54726348; COSMIC: COSV54726348;