rs11554620

Positions:

chr16-74716453-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The ENST00000219368.8(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
ENST00000219368.8 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: -0.0720

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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	Protein
FA2H	NM_024306.5 linkuse as main transcript	c.933T>C	p.Tyr311=	synonymous_variant	6/7	ENST00000219368.8	NP_077282.3
FA2H	XM_011523319.3 linkuse as main transcript	c.693T>C	p.Tyr231=	synonymous_variant	6/7		XP_011521621.1
FA2H	XM_011523317.4 linkuse as main transcript	c.*1797T>C		3_prime_UTR_variant	6/6		XP_011521619.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FA2H	ENST00000219368.8 linkuse as main transcript	c.933T>C	p.Tyr311=	synonymous_variant	6/7	1	NM_024306.5	ENSP00000219368	P1	Q7L5A8-1
FA2H	ENST00000562145.1 linkuse as main transcript	n.654T>C		non_coding_transcript_exon_variant	1/2	1
FA2H	ENST00000567683.5 linkuse as main transcript	c.*212T>C		3_prime_UTR_variant, NMD_transcript_variant	4/5	2		ENSP00000455126

Frequencies

GnomAD3 genomes

AF:

0.0771

AC:

11716

AN:

151860

Hom.:

940

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.0337

AC XY:

24504

AN XY:

727224

show subpopulations

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.:

AF XY:

0.0744

AC XY:

5528

AN XY:

74310

show subpopulations

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:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
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+	-	- -

Spastic paraplegia

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

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

- -

not provided

Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over