16-74713786-A-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_024306.5(FA2H):c.*404T>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0668 in 198,208 control chromosomes in the GnomAD database, including 1,210 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.078 (1137 hom., cov: 33)
  • Exomes 𝑓: 0.029 (73 hom.)
• Consequence: FA2H NM_024306.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.939

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 16-74713786-A-T is Benign according to our data. Variant chr16-74713786-A-T is described in ClinVar as [Benign]. Clinvar id is 320481.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.222 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FA2H	NM_024306.5	c.*404T>A		3_prime_UTR_variant	7/7	ENST00000219368.8
FA2H	XM_011523319.3	c.*404T>A		3_prime_UTR_variant	7/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FA2H	ENST00000219368.8	c.*404T>A		3_prime_UTR_variant	7/7	1	NM_024306.5	P1
FA2H	ENST00000562145.1	n.1244T>A		non_coding_transcript_exon_variant	2/2	1
FA2H	ENST00000567683.5	c.*802T>A		3_prime_UTR_variant, NMD_transcript_variant	5/5	2

Frequencies

GnomAD3 genomes AF: 0.0782 AC: 11902 AN: 152204 Hom.: 1132 Cov.: 33

Gnomad AFR AF: 0.226

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.0334

Gnomad ASJ AF: 0.00663

Gnomad EAS AF: 0.0655

Gnomad SAS AF: 0.0130

Gnomad FIN AF: 0.00678

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.0203

Gnomad OTH AF: 0.0597

GnomAD4 exome AF: 0.0287 AC: 1319 AN: 45886 Hom.: 73 Cov.: 0 AF XY: 0.0269 AC XY: 639 AN XY: 23782

Gnomad4 AFR exome AF: 0.205

Gnomad4 AMR exome AF: 0.0256

Gnomad4 ASJ exome AF: 0.00653

Gnomad4 EAS exome AF: 0.0624

Gnomad4 SAS exome AF: 0.00646

Gnomad4 FIN exome AF: 0.00686

Gnomad4 NFE exome AF: 0.0177

Gnomad4 OTH exome AF: 0.0283

GnomAD4 genome AF: 0.0783 AC: 11921 AN: 152322 Hom.: 1137 Cov.: 33 AF XY: 0.0748 AC XY: 5573 AN XY: 74478

Gnomad4 AFR AF: 0.226

Gnomad4 AMR AF: 0.0333

Gnomad4 ASJ AF: 0.00663

Gnomad4 EAS AF: 0.0656

Gnomad4 SAS AF: 0.0126

Gnomad4 FIN AF: 0.00678

Gnomad4 NFE AF: 0.0203

Gnomad4 OTH AF: 0.0581

Alfa AF: 0.00454 Hom.: 2

Bravo AF: 0.0875

Asia WGS AF: 0.0490 AC: 172 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
Cadd	Benign	0.42
Dann	Benign	0.52

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: rs73614641; hg19: chr16-74747684; COSMIC: COSV54726148;