16-74714197-G-T

Variant names:

• chr16-74714197-G-T
• NM_024306.5:c.1112C>A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_024306.5(FA2H):​c.1112C>A​(p.Thr371Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000071 in 1,408,392 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: FA2H NM_024306.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0940

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 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=0.04982859).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FA2H	NM_024306.5	c.1112C>A	p.Thr371Lys	missense_variant	Exon 7 of 7	ENST00000219368.8	NP_077282.3
FA2H	XM_011523319.3	c.872C>A	p.Thr291Lys	missense_variant	Exon 7 of 7		XP_011521621.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FA2H	ENST00000219368.8	c.1112C>A	p.Thr371Lys	missense_variant	Exon 7 of 7	1	NM_024306.5	ENSP00000219368.3
FA2H	ENST00000562145.1	n.833C>A		non_coding_transcript_exon_variant	Exon 2 of 2	1
FA2H	ENST00000567683.5	n.*391C>A		non_coding_transcript_exon_variant	Exon 5 of 5	2		ENSP00000455126.1
FA2H	ENST00000567683.5	n.*391C>A		3_prime_UTR_variant	Exon 5 of 5	2		ENSP00000455126.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.10e-7 AC: 1 AN: 1408392 Hom.: 0 Cov.: 30 AF XY: 0.00000144 AC XY: 1 AN XY: 695796

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 9.23e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.063	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	4.8
DANN	Benign	0.91
DEOGEN2	Benign	0.10	T
Eigen	Benign	-0.69
Eigen_PC	Benign	-0.75
FATHMM_MKL	Benign	0.036	N
LIST_S2	Benign	0.39	T
M_CAP	Benign	0.082	D
MetaRNN	Benign	0.050	T
MetaSVM	Benign	-0.68	T
MutationAssessor	Uncertain	2.1	M
PrimateAI	Benign	0.32	T
PROVEAN	Benign	0.42	N
REVEL	Benign	0.10
Sift	Benign	0.039	D
Sift4G	Benign	0.30	T
Polyphen		0.50	P
Vest4		0.077
MutPred		0.23		Loss of ubiquitination at K370 (P = 0.0148);
MVP		0.30
MPC		0.27
ClinPred		0.14	T
GERP RS		-0.41
Varity_R		0.042
gMVP		0.58

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.

Other links and lift over

hg19: chr16-74748095;