16-74716498-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_024306.5(FA2H):c.888A>G(p.Val296Val) 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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 1.30

Publications

10 publications found

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 Gene-Disease associations (from GenCC):

hereditary spastic paraplegia 35
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae), G2P

FA2H links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId is 129032.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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 rank	MANE	Protein	UniProt
FA2H	NM_024306.5 link	c.888A>G	p.Val296Val	synonymous_variant	Exon 6 of 7	ENST00000219368.8	NP_077282.3	Q7L5A8-1
FA2H	XM_011523319.3 link	c.648A>G	p.Val216Val	synonymous_variant	Exon 6 of 7		XP_011521621.1
FA2H	XM_011523317.4 link	c.*1752A>G		3_prime_UTR_variant	Exon 6 of 6		XP_011521619.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
FA2H	ENST00000219368.8 link	c.888A>G	p.Val296Val	synonymous_variant	Exon 6 of 7	1	NM_024306.5	ENSP00000219368.3	Q7L5A8-1
FA2H	ENST00000562145.1 link	n.609A>G		non_coding_transcript_exon_variant	Exon 1 of 2	1
FA2H	ENST00000567683.5 link	n.*167A>G		non_coding_transcript_exon_variant	Exon 4 of 5	2		ENSP00000455126.1	H3BP32
FA2H	ENST00000567683.5 link	n.*167A>G		3_prime_UTR_variant	Exon 4 of 5	2		ENSP00000455126.1	H3BP32

Frequencies

GnomAD3 genomes

AF:

0.153

AC:

23221

AN:

151608

Hom.:

1990

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.116

AC:

29064

AN:

250082

AF XY:

0.115

show subpopulations

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 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.:

AF XY:

0.142

AC XY:

103185

AN XY:

727086

show subpopulations

African (AFR)

AF:

0.222

AC:

7430

AN:

33476

American (AMR)

AF:

0.0816

AC:

3648

AN:

44680

Ashkenazi Jewish (ASJ)

AF:

0.104

AC:

2725

AN:

26130

East Asian (EAS)

AF:

0.0410

AC:

1627

AN:

39694

South Asian (SAS)

AF:

0.0607

AC:

5235

AN:

86232

European-Finnish (FIN)

AF:

0.0631

AC:

3369

AN:

53386

Middle Eastern (MID)

AF:

0.128

AC:

738

AN:

5768

European-Non Finnish (NFE)

AF:

0.160

AC:

178156

AN:

1111842

Other (OTH)

AF:

0.139

AC:

8391

AN:

60376

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

10247

20494

30741

40988

51235

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

6352

12704

19056

25408

31760

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.153

AC:

23268

AN:

151726

Hom.:

2000

Cov.:

AF XY:

0.145

AC XY:

10779

AN XY:

74152

show subpopulations

African (AFR)

AF:

0.220

AC:

9115

AN:

41340

American (AMR)

AF:

0.115

AC:

1745

AN:

15232

Ashkenazi Jewish (ASJ)

AF:

0.105

AC:

364

AN:

3466

East Asian (EAS)

AF:

0.0488

AC:

247

AN:

5066

South Asian (SAS)

AF:

0.0666

AC:

320

AN:

4804

European-Finnish (FIN)

AF:

0.0586

AC:

619

AN:

10570

Middle Eastern (MID)

AF:

0.0918

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.153

AC:

10379

AN:

67942

Other (OTH)

AF:

0.157

AC:

329

AN:

2100

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

971

1943

2914

3886

4857

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

240

480

720

960

1200

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.155

Hom.:

3456

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:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Aug 15, 2013

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Feb 24, 2016

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Hereditary spastic paraplegia 35

Benign:3

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Sep 21, 2015

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Sep 21, 2015

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Spastic paraplegia

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hereditary spastic paraplegia

Benign:1

Dec 12, 2016

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.65

CADD

Benign

9.9

(source)

DANN

Benign

0.70

PhyloP100

1.3

Mutation Taster

=95/5

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over