16-74734914-G-T

Position:

• chr16-74734914-G-T

Variant summary

Our verdict is Benign. Variant got -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

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]

ACMG classification

Verdict is Benign. Variant got -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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FA2H	NM_024306.5	c.363+5109C>A		intron_variant		ENST00000219368.8	NP_077282.3
FA2H	XM_011523317.4	c.363+5109C>A		intron_variant			XP_011521619.1
FA2H	XM_011523319.3	c.123+5109C>A		intron_variant			XP_011521621.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FA2H	ENST00000219368.8	c.363+5109C>A		intron_variant		1	NM_024306.5	ENSP00000219368.3
FA2H	ENST00000569949.1	c.165+5109C>A		intron_variant		4		ENSP00000464576.1
FA2H	ENST00000567683.5	n.363+5109C>A		intron_variant		2		ENSP00000455126.1

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

Gnomad4 AFR AF: 0.203

Gnomad4 AMR AF: 0.253

Gnomad4 ASJ AF: 0.264

Gnomad4 EAS AF: 0.427

Gnomad4 SAS AF: 0.291

Gnomad4 FIN AF: 0.311

Gnomad4 NFE AF: 0.253

Gnomad4 OTH AF: 0.273

Alfa AF: 0.258 Hom.: 10180

Bravo AF: 0.245

Asia WGS AF: 0.326 AC: 1130 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	7.2
DANN	Benign	0.82

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

Publications

LitVar

Other links and lift over

dbSNP: rs1076251; hg19: chr16-74768812; COSMIC: COSV54728246;