16-74713670-C-T

Variant names:

• chr16-74713670-C-T
• rs187456324
• ENST00000562145.1:n.1360G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_024306.5(FA2H):​c.*520G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00494 in 156,930 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0049 (3 hom., cov: 33)
  • Exomes 𝑓: 0.0057 (0 hom.)
• Consequence: FA2H NM_024306.5 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.965
• 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 16-74713670-C-T is Benign according to our data. Variant chr16-74713670-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 320478.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00492 (749/152346) while in subpopulation NFE AF = 0.00753 (512/68028). AF 95% confidence interval is 0.00699. There are 3 homozygotes in GnomAd4. There are 355 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FA2H	NM_024306.5	c.*520G>A		3_prime_UTR_variant	Exon 7 of 7	ENST00000219368.8	NP_077282.3
FA2H	XM_011523319.3	c.*520G>A		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.1360G>A		non_coding_transcript_exon_variant	Exon 2 of 2	1
FA2H	ENST00000219368.8	c.*520G>A		3_prime_UTR_variant	Exon 7 of 7	1	NM_024306.5	ENSP00000219368.3
FA2H	ENST00000567683.5	n.*918G>A		non_coding_transcript_exon_variant	Exon 5 of 5	2		ENSP00000455126.1
FA2H	ENST00000567683.5	n.*918G>A		3_prime_UTR_variant	Exon 5 of 5	2		ENSP00000455126.1

Frequencies

GnomAD3 genomes AF: 0.00492 AC: 749 AN: 152228 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.00111

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00700

Gnomad ASJ AF: 0.00634

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.00320

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.00753

Gnomad OTH AF: 0.00860

GnomAD4 exome AF: 0.00567 AC: 26 AN: 4584 Hom.: 0 Cov.: 0 AF XY: 0.00581 AC XY: 14 AN XY: 2408

African (AFR) AF: 0.00 AC: 0 AN: 96

American (AMR) AF: 0.00509 AC: 5 AN: 982

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24

East Asian (EAS) AF: 0.00 AC: 0 AN: 278

South Asian (SAS) AF: 0.00298 AC: 1 AN: 336

European-Finnish (FIN) AF: 0.00943 AC: 3 AN: 318

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 6

European-Non Finnish (NFE) AF: 0.00723 AC: 17 AN: 2352

Other (OTH) AF: 0.00 AC: 0 AN: 192

GnomAD4 genome AF: 0.00492 AC: 749 AN: 152346 Hom.: 3 Cov.: 33 AF XY: 0.00477 AC XY: 355 AN XY: 74496

African (AFR) AF: 0.00111 AC: 46 AN: 41572

American (AMR) AF: 0.00699 AC: 107 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00634 AC: 22 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00186 AC: 9 AN: 4830

European-Finnish (FIN) AF: 0.00320 AC: 34 AN: 10630

Middle Eastern (MID) AF: 0.00342 AC: 1 AN: 292

European-Non Finnish (NFE) AF: 0.00753 AC: 512 AN: 68028

Other (OTH) AF: 0.00851 AC: 18 AN: 2116

Alfa AF: 0.00603 Hom.: 0

Bravo AF: 0.00510

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary spastic paraplegia 35 Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	2.1
DANN	Benign	0.68
PhyloP100		-0.96

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: rs187456324; hg19: chr16-74747568;