rs6564160

Positions:

chr16-74716339-A-G

Variant summary

Our verdict is Benign. Variant got -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:8

Conservation

PhyloP100: -3.71

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 -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 id is 129027.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-74716339-A-G is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.252 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.1039+8T>C		splice_region_variant, intron_variant		ENST00000219368.8	NP_077282.3
FA2H	XM_011523319.3 linkuse as main transcript	c.799+8T>C		splice_region_variant, intron_variant			XP_011521621.1

Ensembl

Gene	Transcript	HGVSc	Effect	TSL	MANE	Protein	Appris	UniProt
FA2H	ENST00000219368.8 linkuse as main transcript	c.1039+8T>C	splice_region_variant, intron_variant	1	NM_024306.5	ENSP00000219368	P1	Q7L5A8-1
FA2H	ENST00000562145.1 linkuse as main transcript	n.760+8T>C	splice_region_variant, intron_variant, non_coding_transcript_variant	1
FA2H	ENST00000567683.5 linkuse as main transcript	c.*318+8T>C	splice_region_variant, intron_variant, NMD_transcript_variant	2		ENSP00000455126

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

GnomAD3 exomes

AF:

0.0419

AC:

10490

AN:

250256

Hom.:

677

AF XY:

0.0373

AC XY:

5048

AN XY:

135280

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 SAS exome

AF:

0.0145

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

Gnomad4 AFR exome

AF:

0.267

Gnomad4 AMR exome

AF:

0.0255

Gnomad4 ASJ exome

AF:

0.00812

Gnomad4 EAS exome

AF:

0.0408

Gnomad4 SAS exome

AF:

0.0147

Gnomad4 FIN exome

AF:

0.0126

Gnomad4 NFE exome

AF:

0.0327

Gnomad4 OTH exome

AF:

0.0442

GnomAD4 genome

AF:

0.0921

AC:

13992

AN:

151918

Hom.:

1411

Cov.:

AF XY:

0.0886

AC XY:

6581

AN XY:

74282

show subpopulations

Gnomad4 AFR

AF:

0.256

Gnomad4 AMR

AF:

0.0433

Gnomad4 ASJ

AF:

0.00634

Gnomad4 EAS

AF:

0.0474

Gnomad4 SAS

AF:

0.0189

Gnomad4 FIN

AF:

0.0131

Gnomad4 NFE

AF:

0.0303

Gnomad4 OTH

AF:

0.0692

Alfa

AF:

0.0604

Hom.:

405

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:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

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

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

-0.90

CADD

Benign

0.12

DANN

Benign

0.35

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

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