dbSNP rs35874850: FA2H:p.Pro97Ser (chr16-74740097-G-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_024306.5(FA2H):c.289C>T(p.Pro97Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,398 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 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. P97A) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

FA2H
NM_024306.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.690

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.040974647).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FA2H	NM_024306.5 link	c.289C>T	p.Pro97Ser	missense_variant	Exon 2 of 7	ENST00000219368.8	NP_077282.3	Q7L5A8-1
FA2H	XM_011523317.4 link	c.289C>T	p.Pro97Ser	missense_variant	Exon 2 of 6		XP_011521619.1
FA2H	XM_011523319.3 link	c.49C>T	p.Pro17Ser	missense_variant	Exon 2 of 7		XP_011521621.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
FA2H	ENST00000219368.8 link	c.289C>T	p.Pro97Ser	missense_variant	Exon 2 of 7	1	NM_024306.5	ENSP00000219368.3	Q7L5A8-1
FA2H	ENST00000569949.1 link	c.91C>T	p.Pro31Ser	missense_variant	Exon 2 of 5	4		ENSP00000464576.1	J3QS89
FA2H	ENST00000567683.5 link	n.289C>T		non_coding_transcript_exon_variant	Exon 2 of 5	2		ENSP00000455126.1	H3BP32

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461398

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727040

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.067

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Benign

-0.47

CADD

Benign

0.99

DANN

Benign

0.78

DEOGEN2

Benign

0.089

T;T

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.019

LIST_S2

Benign

0.25

T;T

M_CAP

Benign

0.046

MetaRNN

Benign

0.041

T;T

MetaSVM

Benign

-0.88

MutationAssessor

Benign

0.55

N;.

PrimateAI

Benign

0.29

PROVEAN

Benign

0.10

N;.

REVEL

Benign

0.12

Sift

Benign

0.74

T;.

Sift4G

Benign

0.79

T;.

Polyphen

0.0010

B;.

Vest4

0.060

MutPred

0.23

Gain of phosphorylation at P97 (P = 0.0458);.;

MVP

0.44

MPC

0.22

ClinPred

0.019

GERP RS

-1.2

Varity_R

0.019

gMVP

0.18

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over