Genetic Variant NM_024306.5:c.1055C>A (chr16-74714254-G-T) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_024306.5(FA2H):c.1055C>A(p.Thr352Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/22 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. T352I) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

FA2H
NM_024306.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.55

Publications

2 publications found

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 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

FA2H links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.32196885).

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.1055C>A	p.Thr352Asn	missense	Exon 7 of 7	NP_077282.3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
FA2H	ENST00000219368.8	TSL:1 MANE Select	c.1055C>A	p.Thr352Asn	missense	Exon 7 of 7	ENSP00000219368.3
FA2H	ENST00000562145.1	TSL:1	n.776C>A		non_coding_transcript_exon	Exon 2 of 2
FA2H	ENST00000888352.1		c.1049C>A	p.Thr350Asn	missense	Exon 7 of 7	ENSP00000558411.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000593

AC:

AN:

168580

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.000102

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1408768

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

695888

African (AFR)

AF:

0.00

AC:

AN:

32022

American (AMR)

AF:

0.00

AC:

AN:

37042

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25258

East Asian (EAS)

AF:

0.00

AC:

AN:

36574

South Asian (SAS)

AF:

0.00

AC:

AN:

79808

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50140

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5700

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1083768

Other (OTH)

AF:

0.00

AC:

AN:

58456

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ESP6500AA

AF:

0.000228

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00000858

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

0.011

BayesDel_noAF

Benign

-0.22

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.32

Eigen

Benign

-0.097

Eigen_PC

Benign

-0.069

FATHMM_MKL

Uncertain

0.87

LIST_S2

Uncertain

0.86

M_CAP

Uncertain

0.12

MetaRNN

Benign

0.32

MetaSVM

Uncertain

-0.25

MutationAssessor

Benign

1.9

PhyloP100

1.5

PrimateAI

Benign

0.33

PROVEAN

Benign

-1.4

REVEL

Benign

0.29

Sift

Uncertain

0.0080

Sift4G

Uncertain

0.010

Polyphen

0.97

Vest4

0.45

MVP

0.70

MPC

0.48

ClinPred

0.35

GERP RS

2.1

Varity_R

0.32

gMVP

0.85

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over