rs2301865

Positions:

Variant summary

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

The NM_024306.5(FA2H):c.879C>T(p.Pro293Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.797 in 1,612,910 control chromosomes in the GnomAD database, including 514,126 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.77 ( 45600 hom., cov: 29)

Exomes 𝑓: 0.80 ( 468526 hom. )

Consequence

FA2H
NM_024306.5 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: -2.58

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:

FA2H (HGNC:):

FA2H links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.75).

BP6

Variant 16-74716507-G-A is Benign according to our data. Variant chr16-74716507-G-A is described in ClinVar as [Benign]. Clinvar id is 129031.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-74716507-G-A is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-2.58 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.809 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FA2H	NM_024306.5 linkuse as main transcript	c.879C>T	p.Pro293Pro	synonymous_variant	6/7	ENST00000219368.8	NP_077282.3	Q7L5A8-1
FA2H	XM_011523319.3 linkuse as main transcript	c.639C>T	p.Pro213Pro	synonymous_variant	6/7		XP_011521621.1
FA2H	XM_011523317.4 linkuse as main transcript	c.*1743C>T		3_prime_UTR_variant	6/6		XP_011521619.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
FA2H	ENST00000219368.8 linkuse as main transcript	c.879C>T	p.Pro293Pro	synonymous_variant	6/7	1	NM_024306.5	ENSP00000219368.3	Q7L5A8-1
FA2H	ENST00000562145.1 linkuse as main transcript	n.600C>T		non_coding_transcript_exon_variant	1/2	1
FA2H	ENST00000567683.5 linkuse as main transcript	n.*158C>T		non_coding_transcript_exon_variant	4/5	2		ENSP00000455126.1	H3BP32
FA2H	ENST00000567683.5 linkuse as main transcript	n.*158C>T		3_prime_UTR_variant	4/5	2		ENSP00000455126.1	H3BP32

Frequencies

GnomAD3 genomes

AF:

0.774

AC:

117281

AN:

151562

Hom.:

45581

Cov.:

show subpopulations

Gnomad AFR

AF:

0.715

Gnomad AMI

AF:

0.757

Gnomad AMR

AF:

0.770

Gnomad ASJ

AF:

0.785

Gnomad EAS

AF:

0.665

Gnomad SAS

AF:

0.701

Gnomad FIN

AF:

0.823

Gnomad MID

AF:

0.870

Gnomad NFE

AF:

0.815

Gnomad OTH

AF:

0.794

GnomAD3 exomes

AF:

0.772

AC:

192521

AN:

249406

Hom.:

74774

AF XY:

0.772

AC XY:

104118

AN XY:

134912

show subpopulations

Gnomad AFR exome

AF:

0.711

Gnomad AMR exome

AF:

0.754

Gnomad ASJ exome

AF:

0.795

Gnomad EAS exome

AF:

0.656

Gnomad SAS exome

AF:

0.691

Gnomad FIN exome

AF:

0.831

Gnomad NFE exome

AF:

0.812

Gnomad OTH exome

AF:

0.794

GnomAD4 exome

AF:

0.799

AC:

1167962

AN:

1461230

Hom.:

468526

Cov.:

AF XY:

0.797

AC XY:

579596

AN XY:

726908

show subpopulations

Gnomad4 AFR exome

AF:

0.708

Gnomad4 AMR exome

AF:

0.757

Gnomad4 ASJ exome

AF:

0.791

Gnomad4 EAS exome

AF:

0.652

Gnomad4 SAS exome

AF:

0.702

Gnomad4 FIN exome

AF:

0.831

Gnomad4 NFE exome

AF:

0.815

Gnomad4 OTH exome

AF:

0.792

GnomAD4 genome

AF:

0.774

AC:

117345

AN:

151680

Hom.:

45600

Cov.:

AF XY:

0.772

AC XY:

57233

AN XY:

74098

show subpopulations

Gnomad4 AFR

AF:

0.714

Gnomad4 AMR

AF:

0.770

Gnomad4 ASJ

AF:

0.785

Gnomad4 EAS

AF:

0.666

Gnomad4 SAS

AF:

0.701

Gnomad4 FIN

AF:

0.823

Gnomad4 NFE

AF:

0.815

Gnomad4 OTH

AF:

0.794

Alfa

AF:

0.806

Hom.:

59522

Bravo

AF:

0.768

Asia WGS

AF:

0.677

AC:

2357

AN:

3478

EpiCase

AF:

0.821

EpiControl

AF:

0.818

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hereditary spastic paraplegia 35

Benign:5

Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 10, 2021	- -
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. -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	Jul 24, 2015	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not specified

Benign:4

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+	-	- -
Benign, criteria provided, single submitter	clinical testing	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Jul 31, 2024	This variant is classified as Benign based on local population frequency. This variant was detected in 95% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy, Progressive Myoclonus Epilepsy and Abnormal Movements and Neurodegeneration with brain iron accumulation. Number of patients: 88. Only high quality variants are reported. -
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. -

Spastic paraplegia

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

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

- -

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

-0.75

CADD

Benign

0.014

DANN

Benign

0.73

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