16-74713553-C-G

Variant names:

• chr16-74713553-C-G
• rs56033857
• ENST00000562145.1:n.1477G>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000562145.1(FA2H):​n.1477G>C variant causes a non coding transcript exon 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.30 (7655 hom., cov: 33)
  • Exomes 𝑓: 0.36 (11 hom.)
• Consequence: FA2H ENST00000562145.1 non_coding_transcript_exon
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.972
• Publications: 4 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• 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 rank	MANE	Protein	UniProt
FA2H	NM_024306.5	c.*637G>C		3_prime_UTR_variant	Exon 7 of 7	ENST00000219368.8	NP_077282.3
FA2H	XM_011523319.3	c.*637G>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.1477G>C		non_coding_transcript_exon_variant	Exon 2 of 2	1
FA2H	ENST00000219368.8	c.*637G>C		3_prime_UTR_variant	Exon 7 of 7	1	NM_024306.5	ENSP00000219368.3
FA2H	ENST00000567683.5	n.*1035G>C		downstream_gene_variant		2		ENSP00000455126.1

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

African (AFR) AC: 0 AN: 0

American (AMR) AF: 0.00 AC: 0 AN: 2

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.0833 AC: 1 AN: 12

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.377 AC: 43 AN: 114

Other (OTH) AF: 0.625 AC: 5 AN: 8

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

African (AFR) AF: 0.204 AC: 8462 AN: 41542

American (AMR) AF: 0.354 AC: 5423 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.372 AC: 1292 AN: 3472

East Asian (EAS) AF: 0.0947 AC: 490 AN: 5172

South Asian (SAS) AF: 0.206 AC: 997 AN: 4830

European-Finnish (FIN) AF: 0.343 AC: 3637 AN: 10594

Middle Eastern (MID) AF: 0.363 AC: 106 AN: 292

European-Non Finnish (NFE) AF: 0.365 AC: 24774 AN: 67966

Other (OTH) AF: 0.346 AC: 731 AN: 2110

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

Jan 13, 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. -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.82
DANN	Benign	0.46
PhyloP100		-0.97
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: rs56033857; hg19: chr16-74747451;