16-74740097-G-C

Variant names:

• chr16-74740097-G-C
• rs35874850
• NM_024306.5:c.289C>G

Variant summary

Our verdict is Benign. The variant received -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. 16/21 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
• Publications: 11 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), ClinGen, G2P

ACMG classification

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId is 129029.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdExome4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.053 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FA2H	NM_024306.5	MANE Select	c.289C>G	p.Pro97Ala	missense	Exon 2 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.289C>G	p.Pro97Ala	missense	Exon 2 of 7	ENSP00000219368.3	Q7L5A8-1
	FA2H	ENST00000888352.1		c.289C>G	p.Pro97Ala	missense	Exon 2 of 7	ENSP00000558411.1
	FA2H	ENST00000888351.1		c.289C>G	p.Pro97Ala	missense	Exon 2 of 7	ENSP00000558410.1

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

GnomAD2 exomes AF: 0.00954 AC: 2399 AN: 251494 AF XY: 0.00858

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 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

African (AFR) AF: 0.0551 AC: 1841 AN: 33440

American (AMR) AF: 0.00780 AC: 349 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00337 AC: 88 AN: 26132

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39698

South Asian (SAS) AF: 0.00434 AC: 374 AN: 86246

European-Finnish (FIN) AF: 0.00485 AC: 259 AN: 53408

Middle Eastern (MID) AF: 0.0149 AC: 86 AN: 5768

European-Non Finnish (NFE) AF: 0.00648 AC: 7205 AN: 1111466

Other (OTH) AF: 0.00974 AC: 588 AN: 60358

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

African (AFR) AF: 0.0506 AC: 2100 AN: 41512

American (AMR) AF: 0.00895 AC: 137 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00461 AC: 16 AN: 3472

East Asian (EAS) AF: 0.000387 AC: 2 AN: 5168

South Asian (SAS) AF: 0.00436 AC: 21 AN: 4820

European-Finnish (FIN) AF: 0.00273 AC: 29 AN: 10616

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.00898 AC: 611 AN: 68012

Other (OTH) AF: 0.0180 AC: 38 AN: 2110

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

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Hereditary spastic paraplegia 35 (3)
-	-	3	not specified (3)
-	-	1	Hereditary spastic paraplegia (1)
-	-	1	not provided (1)
-	-	1	Spastic paraplegia (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.0053	N
LIST_S2	Benign	0.21	T
MetaRNN	Benign	0.0019	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	-0.98	N
PhyloP100		-0.69
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
Mutation Taster		=99/1	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: rs35874850; hg19: chr16-74773995;