NM_024306.5:c.229C>T

Variant names:

• chr16-74774527-G-A
• rs929881
• NM_024306.5:c.229C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_024306.5(FA2H):​c.229C>T​(p.Leu77Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.305 in 1,544,230 control chromosomes in the GnomAD database, including 75,258 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.32 (8553 hom., cov: 32)
  • Exomes 𝑓: 0.30 (66705 hom.)
• Consequence: FA2H NM_024306.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 2.61
• Publications: 15 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), ClinGen, G2P

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.5).
• BP6: Variant 16-74774527-G-A is Benign according to our data. Variant chr16-74774527-G-A is described in ClinVar as Benign. ClinVar VariationId is 129028.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=2.61 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.426 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.229C>T	p.Leu77Leu	synonymous	Exon 1 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.229C>T	p.Leu77Leu	synonymous	Exon 1 of 7	ENSP00000219368.3	Q7L5A8-1
	FA2H	ENST00000888352.1		c.229C>T	p.Leu77Leu	synonymous	Exon 1 of 7	ENSP00000558411.1
	FA2H	ENST00000888351.1		c.229C>T	p.Leu77Leu	synonymous	Exon 1 of 7	ENSP00000558410.1

Frequencies

GnomAD3 genomes AF: 0.323 AC: 49093 AN: 151984 Hom.: 8543 Cov.: 32

Gnomad AFR AF: 0.431

Gnomad AMI AF: 0.279

Gnomad AMR AF: 0.251

Gnomad ASJ AF: 0.370

Gnomad EAS AF: 0.0443

Gnomad SAS AF: 0.185

Gnomad FIN AF: 0.248

Gnomad MID AF: 0.342

Gnomad NFE AF: 0.314

Gnomad OTH AF: 0.331

GnomAD2 exomes AF: 0.276 AC: 45677 AN: 165328 AF XY: 0.276

Gnomad AFR exome AF: 0.467

Gnomad AMR exome AF: 0.207

Gnomad ASJ exome AF: 0.398

Gnomad EAS exome AF: 0.0417

Gnomad FIN exome AF: 0.265

Gnomad NFE exome AF: 0.330

Gnomad OTH exome AF: 0.303

GnomAD4 exome AF: 0.303 AC: 421292 AN: 1392126 Hom.: 66705 Cov.: 34 AF XY: 0.299 AC XY: 206082 AN XY: 689134

African (AFR) AF: 0.455 AC: 13840 AN: 30420

American (AMR) AF: 0.211 AC: 7972 AN: 37804

Ashkenazi Jewish (ASJ) AF: 0.371 AC: 8794 AN: 23724

East Asian (EAS) AF: 0.0442 AC: 1582 AN: 35786

South Asian (SAS) AF: 0.176 AC: 13668 AN: 77578

European-Finnish (FIN) AF: 0.253 AC: 9408 AN: 37248

Middle Eastern (MID) AF: 0.327 AC: 1757 AN: 5380

European-Non Finnish (NFE) AF: 0.319 AC: 346871 AN: 1086466

Other (OTH) AF: 0.301 AC: 17400 AN: 57720

GnomAD4 genome AF: 0.323 AC: 49137 AN: 152104 Hom.: 8553 Cov.: 32 AF XY: 0.316 AC XY: 23522 AN XY: 74368

African (AFR) AF: 0.431 AC: 17887 AN: 41502

American (AMR) AF: 0.251 AC: 3839 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.370 AC: 1284 AN: 3470

East Asian (EAS) AF: 0.0442 AC: 228 AN: 5158

South Asian (SAS) AF: 0.184 AC: 890 AN: 4824

European-Finnish (FIN) AF: 0.248 AC: 2633 AN: 10598

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

European-Non Finnish (NFE) AF: 0.314 AC: 21320 AN: 67930

Other (OTH) AF: 0.331 AC: 699 AN: 2114

Alfa AF: 0.315 Hom.: 12002

Bravo AF: 0.327

Asia WGS AF: 0.181 AC: 629 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	4	Hereditary spastic paraplegia 35 (4)
-	-	1	Hereditary spastic paraplegia (1)
-	-	1	not provided (1)
-	-	1	Spastic paraplegia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
CADD	Benign	13
DANN	Benign	0.94
PhyloP100		2.6
PromoterAI		0.027	Neutral
Mutation Taster		=265/35	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: rs929881; hg19: chr16-74808425; COSMIC: COSV54725551;