16-74713126-G-C

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.*1064C>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.305 in 152,558 control chromosomes in the GnomAD database, including 7,494 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.31 (7459 hom., cov: 33)
  • Exomes 𝑓: 0.37 (35 hom.)
• Consequence: FA2H NM_024306.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.18

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=-0.83).
• BP6: Variant 16-74713126-G-C is Benign according to our data. Variant chr16-74713126-G-C is described in ClinVar as [Benign]. Clinvar id is 320466.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.397 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FA2H	NM_024306.5	c.*1064C>G		3_prime_UTR_variant	7/7	ENST00000219368.8
FA2H	XM_011523319.3	c.*1064C>G		3_prime_UTR_variant	7/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FA2H	ENST00000219368.8	c.*1064C>G		3_prime_UTR_variant	7/7	1	NM_024306.5	P1
FA2H	ENST00000562145.1	n.1904C>G		non_coding_transcript_exon_variant	2/2	1

Frequencies

GnomAD3 genomes AF: 0.305 AC: 46375 AN: 152002 Hom.: 7446 Cov.: 33

Gnomad AFR AF: 0.402

Gnomad AMI AF: 0.207

Gnomad AMR AF: 0.207

Gnomad ASJ AF: 0.264

Gnomad EAS AF: 0.0671

Gnomad SAS AF: 0.266

Gnomad FIN AF: 0.332

Gnomad MID AF: 0.335

Gnomad NFE AF: 0.289

Gnomad OTH AF: 0.283

GnomAD4 exome AF: 0.365 AC: 160 AN: 438 Hom.: 35 Cov.: 0 AF XY: 0.361 AC XY: 96 AN XY: 266

Gnomad4 FIN exome AF: 0.367

Gnomad4 NFE exome AF: 0.167

Gnomad4 OTH exome AF: 0.500

GnomAD4 genome AF: 0.305 AC: 46424 AN: 152120 Hom.: 7459 Cov.: 33 AF XY: 0.302 AC XY: 22494 AN XY: 74364

Gnomad4 AFR AF: 0.402

Gnomad4 AMR AF: 0.206

Gnomad4 ASJ AF: 0.264

Gnomad4 EAS AF: 0.0677

Gnomad4 SAS AF: 0.266

Gnomad4 FIN AF: 0.332

Gnomad4 NFE AF: 0.289

Gnomad4 OTH AF: 0.281

Alfa AF: 0.311 Hom.: 906

Bravo AF: 0.297

Asia WGS AF: 0.199 AC: 694 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 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	-0.83
Cadd	Benign	7.2
Dann	Benign	0.29

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: rs1046371; hg19: chr16-74747024; COSMIC: COSV54727948; COSMIC: COSV54727948;