rs6564160

Variant names:

• chr16-74716339-A-G
• rs6564160
• NM_024306.5:c.1039+8T>C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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

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]

ACMG classification

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

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.0918 AC: 13934 AN: 151800 Hom.: 1395 Cov.: 30

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

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.: 30 AF XY: 0.0351 AC XY: 25518 AN XY: 726922

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.: 30 AF XY: 0.0886 AC XY: 6581 AN XY: 74282

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:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

-

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

- -

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

- -

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. -

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
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

Other links and lift over

dbSNP: rs6564160; hg19: chr16-74750237; COSMIC: COSV54726330; COSMIC: COSV54726330;