16-74713907-C-G

Variant names:

• chr16-74713907-C-G
• rs80215625
• ENST00000562145.1:n.1123G>C

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 0 publications found

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]

FA2H Gene-Disease associations (from GenCC):

• hereditary spastic paraplegia 35

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae), G2P

ACMG classification

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
FA2H	NM_024306.5	c.*283G>C		3_prime_UTR_variant	Exon 7 of 7	ENST00000219368.8	NP_077282.3
FA2H	XM_011523319.3	c.*283G>C		3_prime_UTR_variant	Exon 7 of 7		XP_011521621.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FA2H	ENST00000562145.1	n.1123G>C		non_coding_transcript_exon_variant	Exon 2 of 2	1
FA2H	ENST00000219368.8	c.*283G>C		3_prime_UTR_variant	Exon 7 of 7	1	NM_024306.5	ENSP00000219368.3
FA2H	ENST00000567683.5	n.*681G>C		non_coding_transcript_exon_variant	Exon 5 of 5	2		ENSP00000455126.1
FA2H	ENST00000567683.5	n.*681G>C		3_prime_UTR_variant	Exon 5 of 5	2		ENSP00000455126.1

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

African (AFR) AF: 0.205 AC: 1957 AN: 9530

American (AMR) AF: 0.0150 AC: 202 AN: 13422

Ashkenazi Jewish (ASJ) AF: 0.00352 AC: 32 AN: 9084

East Asian (EAS) AF: 0.00 AC: 0 AN: 21346

South Asian (SAS) AF: 0.0133 AC: 289 AN: 21690

European-Finnish (FIN) AF: 0.0163 AC: 291 AN: 17870

Middle Eastern (MID) AF: 0.0253 AC: 32 AN: 1266

European-Non Finnish (NFE) AF: 0.00499 AC: 844 AN: 169082

Other (OTH) AF: 0.0202 AC: 349 AN: 17264

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

African (AFR) AF: 0.205 AC: 8504 AN: 41496

American (AMR) AF: 0.0214 AC: 327 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00346 AC: 12 AN: 3472

East Asian (EAS) AF: 0.000388 AC: 2 AN: 5156

South Asian (SAS) AF: 0.0137 AC: 66 AN: 4822

European-Finnish (FIN) AF: 0.0167 AC: 177 AN: 10620

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.00513 AC: 349 AN: 68024

Other (OTH) AF: 0.0402 AC: 85 AN: 2112

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

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jul 17, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary spastic paraplegia 35 Benign:1

Jan 12, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	4.3
DANN	Benign	0.61
PhyloP100		0.32
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs80215625; hg19: chr16-74747805;