Genetic Variant FA2H:p.Thr371Thr (chr16-74714196-C-T) – ACMG Classification: Likely_benign (-5 pts)

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 2P and 7B. PM2BP4_StrongBP6_ModerateBP7

The NM_024306.5(FA2H):c.1113G>A(p.Thr371Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000284 in 1,407,578 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Synonymous variant affecting the same amino acid position (i.e. T371T) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000028 ( 0 hom. )

Consequence

FA2H
NM_024306.5 synonymous

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -1.71

Publications

0 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: Likely_benign. The variant received -5 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.57).

BP6

Variant 16-74714196-C-T is Benign according to our data. Variant chr16-74714196-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 2036748.Status of the report is criteria_provided_single_submitter, 1 stars.

BP7

Synonymous conserved (PhyloP=-1.71 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FA2H	NM_024306.5 link	c.1113G>A	p.Thr371Thr	synonymous_variant	Exon 7 of 7	ENST00000219368.8	NP_077282.3	Q7L5A8-1
FA2H	XM_011523319.3 link	c.873G>A	p.Thr291Thr	synonymous_variant	Exon 7 of 7		XP_011521621.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
FA2H	ENST00000219368.8 link	c.1113G>A	p.Thr371Thr	synonymous_variant	Exon 7 of 7	1	NM_024306.5	ENSP00000219368.3	Q7L5A8-1
FA2H	ENST00000562145.1 link	n.834G>A		non_coding_transcript_exon_variant	Exon 2 of 2	1
FA2H	ENST00000567683.5 link	n.*392G>A		non_coding_transcript_exon_variant	Exon 5 of 5	2		ENSP00000455126.1	H3BP32
FA2H	ENST00000567683.5 link	n.*392G>A		3_prime_UTR_variant	Exon 5 of 5	2		ENSP00000455126.1	H3BP32

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000586

AC:

AN:

170614

AF XY:

0.0000111

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000794

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000284

AC:

AN:

1407578

Hom.:

Cov.:

AF XY:

0.00000431

AC XY:

AN XY:

695366

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32024

American (AMR)

AF:

0.00

AC:

AN:

36932

Ashkenazi Jewish (ASJ)

AF:

0.0000396

AC:

AN:

25236

East Asian (EAS)

AF:

0.0000274

AC:

AN:

36562

South Asian (SAS)

AF:

0.00

AC:

AN:

79824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50076

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5618

European-Non Finnish (NFE)

AF:

0.00000185

AC:

AN:

1082900

Other (OTH)

AF:

0.00

AC:

AN:

58406

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Spastic paraplegia

Benign:1

Jul 07, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.57

CADD

Benign

1.9

(source)

DANN

Benign

0.68

PhyloP100

-1.7

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over