NM_024306.5:c.*283G>C

Variant names:

• chr16-74713907-C-G
• rs80215625
• NM_024306.5:c.*283G>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: Orphanet, G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen

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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024306.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FA2H	NM_024306.5	MANE Select	c.*283G>C		3_prime_UTR	Exon 7 of 7	NP_077282.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FA2H	ENST00000219368.8	TSL:1 MANE Select	c.*283G>C		3_prime_UTR	Exon 7 of 7	ENSP00000219368.3	Q7L5A8-1
	FA2H	ENST00000562145.1	TSL:1	n.1123G>C		non_coding_transcript_exon	Exon 2 of 2
	FA2H	ENST00000888352.1		c.*283G>C		3_prime_UTR	Exon 7 of 7	ENSP00000558411.1

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

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Hereditary spastic paraplegia 35 (1)

Computational scores

Source: dbNSFP v4.9

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;