16-74740097-G-C

Position:

• chr16-74740097-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_024306.5(FA2H):​c.289C>G​(p.Pro97Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00852 in 1,613,458 control chromosomes in the GnomAD database, including 166 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.019 (65 hom., cov: 31)
  • Exomes 𝑓: 0.0074 (101 hom.)
• Consequence: FA2H NM_024306.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.690

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0018601716).
• BP6: Variant 16-74740097-G-C is Benign according to our data. Variant chr16-74740097-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 129029.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-74740097-G-C is described in Lovd as [Likely_benign].
• BA1: GnomAdExome4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.053 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FA2H	NM_024306.5	c.289C>G	p.Pro97Ala	missense_variant	2/7	ENST00000219368.8	NP_077282.3
FA2H	XM_011523317.4	c.289C>G	p.Pro97Ala	missense_variant	2/6		XP_011521619.1
FA2H	XM_011523319.3	c.49C>G	p.Pro17Ala	missense_variant	2/7		XP_011521621.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FA2H	ENST00000219368.8	c.289C>G	p.Pro97Ala	missense_variant	2/7	1	NM_024306.5	ENSP00000219368.3
FA2H	ENST00000569949.1	c.91C>G	p.Pro31Ala	missense_variant	2/5	4		ENSP00000464576.1
FA2H	ENST00000567683.5	n.289C>G		non_coding_transcript_exon_variant	2/5	2		ENSP00000455126.1

Frequencies

GnomAD3 genomes AF: 0.0194 AC: 2950 AN: 152100 Hom.: 64 Cov.: 31

Gnomad AFR AF: 0.0506

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00896

Gnomad ASJ AF: 0.00461

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.00456

Gnomad FIN AF: 0.00273

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00897

Gnomad OTH AF: 0.0177

GnomAD3 exomes AF: 0.00954 AC: 2399 AN: 251494 Hom.: 45 AF XY: 0.00858 AC XY: 1166 AN XY: 135920

Gnomad AFR exome AF: 0.0550

Gnomad AMR exome AF: 0.00702

Gnomad ASJ exome AF: 0.00327

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00431

Gnomad FIN exome AF: 0.00554

Gnomad NFE exome AF: 0.00820

Gnomad OTH exome AF: 0.00717

GnomAD4 exome AF: 0.00739 AC: 10792 AN: 1461240 Hom.: 101 Cov.: 31 AF XY: 0.00723 AC XY: 5257 AN XY: 726976

Gnomad4 AFR exome AF: 0.0551

Gnomad4 AMR exome AF: 0.00780

Gnomad4 ASJ exome AF: 0.00337

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00434

Gnomad4 FIN exome AF: 0.00485

Gnomad4 NFE exome AF: 0.00648

Gnomad4 OTH exome AF: 0.00974

GnomAD4 genome AF: 0.0194 AC: 2958 AN: 152218 Hom.: 65 Cov.: 31 AF XY: 0.0183 AC XY: 1364 AN XY: 74438

Gnomad4 AFR AF: 0.0506

Gnomad4 AMR AF: 0.00895

Gnomad4 ASJ AF: 0.00461

Gnomad4 EAS AF: 0.000387

Gnomad4 SAS AF: 0.00436

Gnomad4 FIN AF: 0.00273

Gnomad4 NFE AF: 0.00898

Gnomad4 OTH AF: 0.0180

Alfa AF: 0.00758 Hom.: 6

Bravo AF: 0.0215

TwinsUK AF: 0.00512 AC: 19

ALSPAC AF: 0.00597 AC: 23

ESP6500AA AF: 0.0573 AC: 252

ESP6500EA AF: 0.00756 AC: 65

ExAC AF: 0.0109 AC: 1322

Asia WGS AF: 0.0210 AC: 73 AN: 3478

EpiCase AF: 0.0101

EpiControl AF: 0.0100

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 15, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 28, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

Hereditary spastic paraplegia 35 Benign:3

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	Jul 24, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 09, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Spastic paraplegia Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

Hereditary spastic paraplegia Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

May 13, 2021

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.046
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	0.20
DANN	Benign	0.55
DEOGEN2	Benign	0.089	T;T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.0053	N
LIST_S2	Benign	0.21	T;T
MetaRNN	Benign	0.0019	T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	-0.98	N;.
PrimateAI	Benign	0.30	T
PROVEAN	Benign	0.26	N;.
REVEL	Benign	0.17
Sift	Benign	0.79	T;.
Sift4G	Benign	0.83	T;.
Polyphen		0.0	B;.
Vest4		0.020
MPC		0.21
ClinPred		0.00014	T
GERP RS		-1.2
Varity_R		0.019
gMVP		0.19

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: rs35874850; hg19: chr16-74773995;