16-74774662-G-T

Variant names:

• chr16-74774662-G-T
• rs978032580
• NM_024306.5:c.94C>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 4P and 1B. PM1 PM2 BP4

The NM_024306.5(FA2H):​c.94C>A​(p.Arg32Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000139 in 1,437,936 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R32G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 7.8e-7 (0 hom.)
• Consequence: FA2H NM_024306.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.56
• 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: Uncertain_significance. The variant received 3 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_024306.5
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.36953157).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FA2H	NM_024306.5	c.94C>A	p.Arg32Ser	missense_variant	Exon 1 of 7	ENST00000219368.8	NP_077282.3
FA2H	XM_011523317.4	c.94C>A	p.Arg32Ser	missense_variant	Exon 1 of 6		XP_011521619.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FA2H	ENST00000219368.8	c.94C>A	p.Arg32Ser	missense_variant	Exon 1 of 7	1	NM_024306.5	ENSP00000219368.3
FA2H	ENST00000567683.5	n.94C>A		non_coding_transcript_exon_variant	Exon 1 of 5	2		ENSP00000455126.1

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152084 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.00 AC: 0 AN: 68276 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 7.78e-7 AC: 1 AN: 1285852 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 632382

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 26388

American (AMR) AF: 0.00 AC: 0 AN: 23610

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22352

East Asian (EAS) AF: 0.00 AC: 0 AN: 27860

South Asian (SAS) AF: 0.00 AC: 0 AN: 65334

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 32414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3864

European-Non Finnish (NFE) AF: 9.70e-7 AC: 1 AN: 1030846

Other (OTH) AF: 0.00 AC: 0 AN: 53184

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 152084 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74298

African (AFR) AF: 0.00 AC: 0 AN: 41458

American (AMR) AF: 0.00 AC: 0 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10578

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67976

Other (OTH) AF: 0.000478 AC: 1 AN: 2092

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.34
BayesDel_addAF	Benign	-0.020	T
BayesDel_noAF	Benign	-0.27
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.40	T
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.24
FATHMM_MKL	Benign	0.23	N
LIST_S2	Benign	0.61	T
M_CAP	Pathogenic	0.97	D
MetaRNN	Benign	0.37	T
MetaSVM	Benign	-0.69	T
MutationAssessor	Benign	1.3	L
PhyloP100		1.6
PrimateAI	Pathogenic	0.94	D
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.18
Sift	Benign	0.18	T
Sift4G	Benign	0.38	T
Polyphen		0.24	B
Vest4		0.18
MutPred		0.61		Loss of MoRF binding (P = 0.025);
MVP		0.093
MPC		2.0
ClinPred		0.68	D
GERP RS		1.9
PromoterAI		-0.044	Neutral
Varity_R		0.26
gMVP		0.78

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: rs978032580; hg19: chr16-74808560;