16-74713907-C-G

Position:

• chr16-74713907-C-G

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.*283G>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0313 in 432,770 control chromosomes in the GnomAD database, including 1,071 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.063 (842 hom., cov: 33)
  • Exomes 𝑓: 0.014 (229 hom.)
• Consequence: FA2H NM_024306.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.316

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 16-74713907-C-G is Benign according to our data. Variant chr16-74713907-C-G is described in ClinVar as [Benign]. Clinvar id is 320484.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.201 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FA2H	NM_024306.5	c.*283G>C		3_prime_UTR_variant	7/7	ENST00000219368.8	NP_077282.3
FA2H	XM_011523319.3	c.*283G>C		3_prime_UTR_variant	7/7		XP_011521621.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FA2H	ENST00000219368.8	c.*283G>C		3_prime_UTR_variant	7/7	1	NM_024306.5	ENSP00000219368	P1
FA2H	ENST00000562145.1	n.1123G>C		non_coding_transcript_exon_variant	2/2	1
FA2H	ENST00000567683.5	c.*681G>C		3_prime_UTR_variant, NMD_transcript_variant	5/5	2		ENSP00000455126

Frequencies

GnomAD3 genomes AF: 0.0626 AC: 9523 AN: 152098 Hom.: 842 Cov.: 33

Gnomad AFR AF: 0.205

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.0214

Gnomad ASJ AF: 0.00346

Gnomad EAS AF: 0.000387

Gnomad SAS AF: 0.0143

Gnomad FIN AF: 0.0167

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.00513

Gnomad OTH AF: 0.0407

GnomAD4 exome AF: 0.0142 AC: 3996 AN: 280554 Hom.: 229 Cov.: 0 AF XY: 0.0133 AC XY: 1918 AN XY: 144366

Gnomad4 AFR exome AF: 0.205

Gnomad4 AMR exome AF: 0.0150

Gnomad4 ASJ exome AF: 0.00352

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0133

Gnomad4 FIN exome AF: 0.0163

Gnomad4 NFE exome AF: 0.00499

Gnomad4 OTH exome AF: 0.0202

GnomAD4 genome AF: 0.0626 AC: 9532 AN: 152216 Hom.: 842 Cov.: 33 AF XY: 0.0608 AC XY: 4529 AN XY: 74432

Gnomad4 AFR AF: 0.205

Gnomad4 AMR AF: 0.0214

Gnomad4 ASJ AF: 0.00346

Gnomad4 EAS AF: 0.000388

Gnomad4 SAS AF: 0.0137

Gnomad4 FIN AF: 0.0167

Gnomad4 NFE AF: 0.00513

Gnomad4 OTH AF: 0.0402

Alfa AF: 0.00312 Hom.: 2

Bravo AF: 0.0701

Asia WGS AF: 0.0140 AC: 47 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 17, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Hereditary spastic paraplegia 35 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	4.3
DANN	Benign	0.61

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

Other links and lift over

dbSNP: rs80215625; hg19: chr16-74747805;