rs367686182

Variant names:

• chr16-74714184-G-C
• rs367686182
• NM_024306.5:c.*6C>G

Your query was ambiguous. Multiple possible variants found:

• chr16-74714184-G-C
• chr16-74714184-G-A

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BS1_Supporting

The NM_024306.5(FA2H):​c.*6C>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000413 in 1,548,954 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 Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00025 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000019 (0 hom.)
• Consequence: FA2H NM_024306.5 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0320
• Publications: 0 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: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00025 (38/152204) while in subpopulation AFR AF = 0.000893 (37/41450). AF 95% confidence interval is 0.000666. There are 0 homozygotes in GnomAd4. There are 22 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

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.*6C>G		3_prime_UTR	Exon 7 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.*6C>G		3_prime_UTR	Exon 7 of 7	ENSP00000219368.3	Q7L5A8-1
	FA2H	ENST00000562145.1	TSL:1	n.846C>G		non_coding_transcript_exon	Exon 2 of 2
	FA2H	ENST00000888352.1		c.*6C>G		3_prime_UTR	Exon 7 of 7	ENSP00000558411.1

Frequencies

GnomAD3 genomes AF: 0.000250 AC: 38 AN: 152204 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000893

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.0000607 AC: 10 AN: 164640 AF XY: 0.0000690

Gnomad AFR exome AF: 0.00106

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 AF: 0.0000186 AC: 26 AN: 1396750 Hom.: 0 Cov.: 29 AF XY: 0.0000145 AC XY: 10 AN XY: 690162

African (AFR) AF: 0.000662 AC: 21 AN: 31728

American (AMR) AF: 0.0000275 AC: 1 AN: 36352

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25168

East Asian (EAS) AF: 0.00 AC: 0 AN: 36164

South Asian (SAS) AF: 0.00 AC: 0 AN: 79396

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49734

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5504

European-Non Finnish (NFE) AF: 0.00000279 AC: 3 AN: 1074706

Other (OTH) AF: 0.0000172 AC: 1 AN: 57998

GnomAD4 genome AF: 0.000250 AC: 38 AN: 152204 Hom.: 0 Cov.: 32 AF XY: 0.000296 AC XY: 22 AN XY: 74358

African (AFR) AF: 0.000893 AC: 37 AN: 41450

American (AMR) AF: 0.00 AC: 0 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68030

Other (OTH) AF: 0.000478 AC: 1 AN: 2094

Alfa AF: 0.0000847 Hom.: 0

Bravo AF: 0.000325

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	7.7
DANN	Benign	0.75
PhyloP100		0.032

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs367686182; hg19: chr16-74748082;