16-74734914-G-T

Variant names:

• chr16-74734914-G-T
• rs1076251
• NM_024306.5:c.363+5109C>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_024306.5(FA2H):​c.363+5109C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.251 in 152,184 control chromosomes in the GnomAD database, including 5,006 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.25 (5006 hom., cov: 33)
• Consequence: FA2H NM_024306.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.29
• 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.413 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FA2H	NM_024306.5	MANE Select	c.363+5109C>A		intron	N/A	NP_077282.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FA2H	ENST00000219368.8	TSL:1 MANE Select	c.363+5109C>A		intron	N/A	ENSP00000219368.3
	FA2H	ENST00000888352.1		c.363+5109C>A		intron	N/A	ENSP00000558411.1
	FA2H	ENST00000888351.1		c.363+5109C>A		intron	N/A	ENSP00000558410.1

Frequencies

GnomAD3 genomes AF: 0.251 AC: 38190 AN: 152066 Hom.: 4993 Cov.: 33

Gnomad AFR AF: 0.203

Gnomad AMI AF: 0.262

Gnomad AMR AF: 0.252

Gnomad ASJ AF: 0.264

Gnomad EAS AF: 0.427

Gnomad SAS AF: 0.291

Gnomad FIN AF: 0.311

Gnomad MID AF: 0.256

Gnomad NFE AF: 0.253

Gnomad OTH AF: 0.270

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.251 AC: 38218 AN: 152184 Hom.: 5006 Cov.: 33 AF XY: 0.255 AC XY: 18959 AN XY: 74416

African (AFR) AF: 0.203 AC: 8419 AN: 41544

American (AMR) AF: 0.253 AC: 3863 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.264 AC: 916 AN: 3468

East Asian (EAS) AF: 0.427 AC: 2203 AN: 5154

South Asian (SAS) AF: 0.291 AC: 1406 AN: 4824

European-Finnish (FIN) AF: 0.311 AC: 3297 AN: 10602

Middle Eastern (MID) AF: 0.248 AC: 73 AN: 294

European-Non Finnish (NFE) AF: 0.253 AC: 17224 AN: 67976

Other (OTH) AF: 0.273 AC: 578 AN: 2114

Alfa AF: 0.255 Hom.: 20846

Bravo AF: 0.245

Asia WGS AF: 0.326 AC: 1130 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	7.2
DANN	Benign	0.82
PhyloP100		1.3
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: rs1076251; hg19: chr16-74768812; COSMIC: COSV54728246;