rs11554620

chr16-74716453-A-G

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.933T>C(p.Tyr311=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0388 in 1,613,832 control chromosomes in the GnomAD database, including 2,564 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.077 (952 hom., cov: 31)
  • Exomes 𝑓: 0.035 (1612 hom.)
• Consequence: FA2H NM_024306.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.0720

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=-0.69).
• BP6: Variant 16-74716453-A-G is Benign according to our data. Variant chr16-74716453-A-G is described in ClinVar as [Benign]. Clinvar id is 129033.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-74716453-A-G is described in Lovd as [Benign]. Variant chr16-74716453-A-G is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-0.072 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.202 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FA2H	NM_024306.5	c.933T>C	p.Tyr311=	synonymous_variant	6/7	ENST00000219368.8
FA2H	XM_011523319.3	c.693T>C	p.Tyr231=	synonymous_variant	6/7
FA2H	XM_011523317.4	c.*1797T>C		3_prime_UTR_variant	6/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FA2H	ENST00000219368.8	c.933T>C	p.Tyr311=	synonymous_variant	6/7	1	NM_024306.5	P1
FA2H	ENST00000562145.1	n.654T>C		non_coding_transcript_exon_variant	1/2	1
FA2H	ENST00000567683.5	c.*212T>C		3_prime_UTR_variant, NMD_transcript_variant	4/5	2

Frequencies

GnomAD3 genomes AF: 0.0771 AC: 11716 AN: 151860 Hom.: 940 Cov.: 31

Gnomad AFR AF: 0.205

Gnomad AMI AF: 0.0263

Gnomad AMR AF: 0.0368

Gnomad ASJ AF: 0.00634

Gnomad EAS AF: 0.0476

Gnomad SAS AF: 0.0193

Gnomad FIN AF: 0.0134

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0301

Gnomad OTH AF: 0.0595

GnomAD3 exomes AF: 0.0377 AC: 9482 AN: 251278 Hom.: 469 AF XY: 0.0342 AC XY: 4639 AN XY: 135826

Gnomad AFR exome AF: 0.205

Gnomad AMR exome AF: 0.0206

Gnomad ASJ exome AF: 0.00744

Gnomad EAS exome AF: 0.0505

Gnomad SAS exome AF: 0.0145

Gnomad FIN exome AF: 0.0113

Gnomad NFE exome AF: 0.0315

Gnomad OTH exome AF: 0.0282

GnomAD4 exome AF: 0.0347 AC: 50785 AN: 1461854 Hom.: 1612 Cov.: 30 AF XY: 0.0337 AC XY: 24504 AN XY: 727224

Gnomad4 AFR exome AF: 0.211

Gnomad4 AMR exome AF: 0.0223

Gnomad4 ASJ exome AF: 0.00811

Gnomad4 EAS exome AF: 0.0409

Gnomad4 SAS exome AF: 0.0146

Gnomad4 FIN exome AF: 0.0126

Gnomad4 NFE exome AF: 0.0327

Gnomad4 OTH exome AF: 0.0401

GnomAD4 genome AF: 0.0774 AC: 11765 AN: 151978 Hom.: 952 Cov.: 31 AF XY: 0.0744 AC XY: 5528 AN XY: 74310

Gnomad4 AFR AF: 0.205

Gnomad4 AMR AF: 0.0368

Gnomad4 ASJ AF: 0.00634

Gnomad4 EAS AF: 0.0479

Gnomad4 SAS AF: 0.0189

Gnomad4 FIN AF: 0.0134

Gnomad4 NFE AF: 0.0301

Gnomad4 OTH AF: 0.0579

Alfa AF: 0.0439 Hom.: 423

Bravo AF: 0.0847

Asia WGS AF: 0.0500 AC: 174 AN: 3478

EpiCase AF: 0.0269

EpiControl AF: 0.0314

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 15, 2013	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 03, 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, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -

Spastic paraplegia Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Hereditary spastic paraplegia 35 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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. -

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	-0.69
Cadd	Benign	1.5
Dann	Benign	0.57

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: rs11554620; hg19: chr16-74750351; COSMIC: COSV54726340; COSMIC: COSV54726340;