rs527421775

Variant names:

• chr16-74774524-C-T
• rs527421775
• NM_024306.5:c.232G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 1P and 1B. PP5 BP4

The NM_024306.5(FA2H):​c.232G>A​(p.Glu78Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000359 in 1,551,336 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00024 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00037 (0 hom.)
• Consequence: FA2H NM_024306.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:8
• Conservation: PhyloP100: 7.05
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PP5: Variant 16-74774524-C-T is Pathogenic according to our data. Variant chr16-74774524-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 320501.
• BP4: Computational evidence support a benign effect (MetaRNN=0.09268516). . Strength limited to SUPPORTING due to the PP5.

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.232G>A	p.Glu78Lys	missense	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.232G>A	p.Glu78Lys	missense	Exon 1 of 7	ENSP00000219368.3
	FA2H	ENST00000888352.1		c.232G>A	p.Glu78Lys	missense	Exon 1 of 7	ENSP00000558411.1
	FA2H	ENST00000888351.1		c.232G>A	p.Glu78Lys	missense	Exon 1 of 7	ENSP00000558410.1

Frequencies

GnomAD3 genomes AF: 0.000237 AC: 36 AN: 152190 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000310 AC: 53 AN: 170850 AF XY: 0.000313

Gnomad AFR exome AF: 0.000109

Gnomad AMR exome AF: 0.000148

Gnomad ASJ exome AF: 0.000426

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000390

Gnomad OTH exome AF: 0.000236

GnomAD4 exome AF: 0.000372 AC: 521 AN: 1399028 Hom.: 0 Cov.: 30 AF XY: 0.000375 AC XY: 260 AN XY: 692990

African (AFR) AF: 0.000129 AC: 4 AN: 30896

American (AMR) AF: 0.000129 AC: 5 AN: 38708

Ashkenazi Jewish (ASJ) AF: 0.000126 AC: 3 AN: 23848

East Asian (EAS) AF: 0.00 AC: 0 AN: 36086

South Asian (SAS) AF: 0.000448 AC: 35 AN: 78134

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 37508

Middle Eastern (MID) AF: 0.000183 AC: 1 AN: 5454

European-Non Finnish (NFE) AF: 0.000424 AC: 462 AN: 1090352

Other (OTH) AF: 0.000190 AC: 11 AN: 58042

GnomAD4 genome AF: 0.000236 AC: 36 AN: 152308 Hom.: 0 Cov.: 32 AF XY: 0.000269 AC XY: 20 AN XY: 74454

African (AFR) AF: 0.000120 AC: 5 AN: 41582

American (AMR) AF: 0.000327 AC: 5 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.000864 AC: 3 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5166

South Asian (SAS) AF: 0.000622 AC: 3 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000294 AC: 20 AN: 68016

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.000300 Hom.: 0

Bravo AF: 0.000223

ExAC AF: 0.000207 AC: 24

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
2	3	-	Hereditary spastic paraplegia 35 (5)
-	2	-	not provided (2)
-	1	-	Hereditary spastic paraplegia (1)
-	1	-	Inborn genetic diseases (1)
-	1	-	not specified (1)
1	-	-	Spastic paraplegia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.48
BayesDel_addAF	Benign	-0.063	T
BayesDel_noAF	Uncertain	0.030
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.21	T
Eigen	Uncertain	0.19
Eigen_PC	Benign	0.20
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.94	D
M_CAP	Pathogenic	0.46	D
MetaRNN	Benign	0.093	T
MetaSVM	Benign	-0.40	T
MutationAssessor	Benign	1.7	L
PhyloP100		7.1
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-0.51	N
REVEL	Uncertain	0.52
Sift	Benign	0.40	T
Sift4G	Benign	0.28	T
Polyphen		0.89	P
Vest4		0.38
MutPred		0.46		Gain of MoRF binding (P = 0.0138)
MVP		0.21
MPC		2.4
ClinPred		0.069	T
GERP RS		3.9
PromoterAI		0.017	Neutral
Varity_R		0.56
gMVP		0.66
Mutation Taster		=187/113	polymorphism

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: rs527421775; hg19: chr16-74808422;