chr16-74716339-A-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_024306.5(FA2H):c.1039+8T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0416 in 1,613,220 control chromosomes in the GnomAD database, including 3,509 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.092 ( 1411 hom., cov: 30)

Exomes 𝑓: 0.036 ( 2098 hom. )

Consequence

FA2H
NM_024306.5 splice_region, intron

Scores

Splicing: ADA: 0.00001405

Clinical Significance

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

Conservation

PhyloP100: -3.71

Publications

6 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.9).

BP6

Variant 16-74716339-A-G is Benign according to our data. Variant chr16-74716339-A-G is described in ClinVar as Benign. ClinVar VariationId is 129027.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.252 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
FA2H	NM_024306.5 link	c.1039+8T>C	splice_region_variant, intron_variant	Intron 6 of 6	ENST00000219368.8	NP_077282.3	Q7L5A8-1
FA2H	XM_011523319.3 link	c.799+8T>C	splice_region_variant, intron_variant	Intron 6 of 6		XP_011521621.1
FA2H	XM_011523317.4 link	c.*1911T>C	downstream_gene_variant			XP_011521619.1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
FA2H	ENST00000219368.8 link	c.1039+8T>C	splice_region_variant, intron_variant	Intron 6 of 6	1	NM_024306.5	ENSP00000219368.3	Q7L5A8-1
FA2H	ENST00000562145.1 link	n.760+8T>C	splice_region_variant, intron_variant	Intron 1 of 1	1
FA2H	ENST00000567683.5 link	n.*318+8T>C	splice_region_variant, intron_variant	Intron 4 of 4	2		ENSP00000455126.1	H3BP32

Frequencies

GnomAD3 genomes

AF:

0.0918

AC:

13934

AN:

151800

Hom.:

1395

Cov.:

show subpopulations

Gnomad AFR

AF:

0.256

Gnomad AMI

AF:

0.0264

Gnomad AMR

AF:

0.0433

Gnomad ASJ

AF:

0.00634

Gnomad EAS

AF:

0.0471

Gnomad SAS

AF:

0.0193

Gnomad FIN

AF:

0.0131

Gnomad MID

AF:

0.0316

Gnomad NFE

AF:

0.0303

Gnomad OTH

AF:

0.0709

GnomAD2 exomes

AF:

0.0419

AC:

10490

AN:

250256

AF XY:

0.0373

show subpopulations

Gnomad AFR exome

AF:

0.262

Gnomad AMR exome

AF:

0.0236

Gnomad ASJ exome

AF:

0.00738

Gnomad EAS exome

AF:

0.0505

Gnomad FIN exome

AF:

0.0112

Gnomad NFE exome

AF:

0.0316

Gnomad OTH exome

AF:

0.0296

GnomAD4 exome

AF:

0.0363

AC:

53069

AN:

1461302

Hom.:

2098

Cov.:

AF XY:

0.0351

AC XY:

25518

AN XY:

726922

show subpopulations

African (AFR)

AF:

0.267

AC:

8944

AN:

33450

American (AMR)

AF:

0.0255

AC:

1142

AN:

44710

Ashkenazi Jewish (ASJ)

AF:

0.00812

AC:

212

AN:

26104

East Asian (EAS)

AF:

0.0408

AC:

1621

AN:

39698

South Asian (SAS)

AF:

0.0147

AC:

1266

AN:

86238

European-Finnish (FIN)

AF:

0.0126

AC:

673

AN:

53392

Middle Eastern (MID)

AF:

0.0329

AC:

190

AN:

5768

European-Non Finnish (NFE)

AF:

0.0327

AC:

36352

AN:

1111560

Other (OTH)

AF:

0.0442

AC:

2669

AN:

60382

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.453

Heterozygous variant carriers

2446

4892

7337

9783

12229

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1520

3040

4560

6080

7600

<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:

0.0921

AC:

13992

AN:

151918

Hom.:

1411

Cov.:

AF XY:

0.0886

AC XY:

6581

AN XY:

74282

show subpopulations

African (AFR)

AF:

0.256

AC:

10598

AN:

41344

American (AMR)

AF:

0.0433

AC:

660

AN:

15252

Ashkenazi Jewish (ASJ)

AF:

0.00634

AC:

AN:

3468

East Asian (EAS)

AF:

0.0474

AC:

244

AN:

5150

South Asian (SAS)

AF:

0.0189

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.0131

AC:

139

AN:

10596

Middle Eastern (MID)

AF:

0.0272

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0303

AC:

2060

AN:

67978

Other (OTH)

AF:

0.0692

AC:

146

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

553

1106

1660

2213

2766

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

136

272

408

544

680

<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:

0.0493

Hom.:

843

Bravo

AF:

0.102

Asia WGS

AF:

0.0550

AC:

193

AN:

3478

EpiCase

AF:

0.0269

EpiControl

AF:

0.0313

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Aug 03, 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. -

Aug 15, 2013

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance:Benign

Review Status:no assertion criteria provided

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

- -

Nov 13, 2023

Athena Diagnostics

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 35

Benign:1

Jan 13, 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. -

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

-0.90

CADD

Benign

0.12

(source)

DANN

Benign

0.35

PhyloP100

-3.7

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000014

dbscSNV1_RF

Benign

0.0040

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