16-74713553-C-G

Position:

• chr16-74713553-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.*637G>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 0.304 in 152,322 control chromosomes in the GnomAD database, including 7,666 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.30 (7655 hom., cov: 33)
  • Exomes 𝑓: 0.36 (11 hom.)
• Consequence: FA2H NM_024306.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.972

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=-0.86).
• BP6: Variant 16-74713553-C-G is Benign according to our data. Variant chr16-74713553-C-G is described in ClinVar as [Benign]. Clinvar id is 320477.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.361 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FA2H	NM_024306.5	c.*637G>C		3_prime_UTR_variant	7/7	ENST00000219368.8
FA2H	XM_011523319.3	c.*637G>C		3_prime_UTR_variant	7/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FA2H	ENST00000219368.8	c.*637G>C		3_prime_UTR_variant	7/7	1	NM_024306.5	P1
FA2H	ENST00000562145.1	n.1477G>C		non_coding_transcript_exon_variant	2/2	1
FA2H	ENST00000567683.5			downstream_gene_variant		2

Frequencies

GnomAD3 genomes AF: 0.304 AC: 46262 AN: 152068 Hom.: 7651 Cov.: 33

Gnomad AFR AF: 0.204

Gnomad AMI AF: 0.415

Gnomad AMR AF: 0.354

Gnomad ASJ AF: 0.372

Gnomad EAS AF: 0.0945

Gnomad SAS AF: 0.206

Gnomad FIN AF: 0.343

Gnomad MID AF: 0.347

Gnomad NFE AF: 0.365

Gnomad OTH AF: 0.348

GnomAD4 exome AF: 0.360 AC: 49 AN: 136 Hom.: 11 Cov.: 0 AF XY: 0.345 AC XY: 29 AN XY: 84

Gnomad4 AMR exome AF: 0.00

Gnomad4 FIN exome AF: 0.0833

Gnomad4 NFE exome AF: 0.377

Gnomad4 OTH exome AF: 0.625

GnomAD4 genome AF: 0.304 AC: 46290 AN: 152186 Hom.: 7655 Cov.: 33 AF XY: 0.302 AC XY: 22482 AN XY: 74414

Gnomad4 AFR AF: 0.204

Gnomad4 AMR AF: 0.354

Gnomad4 ASJ AF: 0.372

Gnomad4 EAS AF: 0.0947

Gnomad4 SAS AF: 0.206

Gnomad4 FIN AF: 0.343

Gnomad4 NFE AF: 0.365

Gnomad4 OTH AF: 0.346

Alfa AF: 0.189 Hom.: 406

Bravo AF: 0.305

Asia WGS AF: 0.168 AC: 584 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

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. -

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	-0.86
CADD	Benign	0.82
DANN	Benign	0.46

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: rs56033857; hg19: chr16-74747451;