ENST00000562145.1:n.1904C>G

Variant names:

• chr16-74713126-G-C
• rs1046371
• ENST00000562145.1:n.1904C>G

Variant summary

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

The ENST00000562145.1(FA2H):​n.1904C>G 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 0.305 in 152,558 control chromosomes in the GnomAD database, including 7,494 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 0.31 (7459 hom., cov: 33)
  • Exomes 𝑓: 0.37 (35 hom.)
• Consequence: FA2H ENST00000562145.1 non_coding_transcript_exon
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.18
• Publications: 7 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=-0.83).
• 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 rank	MANE	Protein	UniProt
FA2H	NM_024306.5	c.*1064C>G		3_prime_UTR_variant	Exon 7 of 7	ENST00000219368.8	NP_077282.3
FA2H	XM_011523319.3	c.*1064C>G		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.1904C>G		non_coding_transcript_exon_variant	Exon 2 of 2	1
FA2H	ENST00000219368.8	c.*1064C>G		3_prime_UTR_variant	Exon 7 of 7	1	NM_024306.5	ENSP00000219368.3

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

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

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: 0.367 AC: 157 AN: 428

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.167 AC: 1 AN: 6

Other (OTH) AF: 0.500 AC: 2 AN: 4

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

African (AFR) AF: 0.402 AC: 16665 AN: 41470

American (AMR) AF: 0.206 AC: 3155 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.264 AC: 916 AN: 3470

East Asian (EAS) AF: 0.0677 AC: 351 AN: 5188

South Asian (SAS) AF: 0.266 AC: 1282 AN: 4826

European-Finnish (FIN) AF: 0.332 AC: 3514 AN: 10578

Middle Eastern (MID) AF: 0.350 AC: 103 AN: 294

European-Non Finnish (NFE) AF: 0.289 AC: 19657 AN: 67982

Other (OTH) AF: 0.281 AC: 592 AN: 2110

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:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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. -

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	-0.83
CADD	Benign	7.2
DANN	Benign	0.29
PhyloP100		2.2
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: rs1046371; hg19: chr16-74747024; COSMIC: COSV54727948; COSMIC: COSV54727948;