rs573058036

Variant names:

• chr16-74713369-G-C
• rs573058036
• NM_024306.5:c.*821C>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_024306.5(FA2H):​c.*821C>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 0.00276 in 152,354 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0028 (3 hom., cov: 33)
  • Exomes 𝑓: 0.0033 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: FA2H NM_024306.5 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.452
• 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: Orphanet, G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 16-74713369-G-C is Benign according to our data. Variant chr16-74713369-G-C is described in ClinVar as Likely_benign. ClinVar VariationId is 320470.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00276 (420/152354) while in subpopulation NFE AF = 0.00288 (196/68046). AF 95% confidence interval is 0.00255. There are 3 homozygotes in GnomAd4. There are 208 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

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.*821C>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.*821C>G		3_prime_UTR	Exon 7 of 7	ENSP00000219368.3	Q7L5A8-1
	FA2H	ENST00000562145.1	TSL:1	n.1661C>G		non_coding_transcript_exon	Exon 2 of 2
	FA2H	ENST00000888352.1		c.*821C>G		3_prime_UTR	Exon 7 of 7	ENSP00000558411.1

Frequencies

GnomAD3 genomes AF: 0.00276 AC: 420 AN: 152236 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.000627

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00137

Gnomad ASJ AF: 0.0256

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00207

Gnomad FIN AF: 0.00640

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00288

Gnomad OTH AF: 0.00430

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00331 AC: 1 AN: 302 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 200

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 4

American (AMR) AF: 0.00 AC: 0 AN: 2

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AF: 0.00 AC: 0 AN: 2

South Asian (SAS) AF: 0.00 AC: 0 AN: 2

European-Finnish (FIN) AF: 0.00649 AC: 1 AN: 154

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 10

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 100

Other (OTH) AF: 0.00 AC: 0 AN: 28

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00276 AC: 420 AN: 152354 Hom.: 3 Cov.: 33 AF XY: 0.00279 AC XY: 208 AN XY: 74498

African (AFR) AF: 0.000625 AC: 26 AN: 41584

American (AMR) AF: 0.00137 AC: 21 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0256 AC: 89 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5184

South Asian (SAS) AF: 0.00208 AC: 10 AN: 4818

European-Finnish (FIN) AF: 0.00640 AC: 68 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00288 AC: 196 AN: 68046

Other (OTH) AF: 0.00426 AC: 9 AN: 2114

Alfa AF: 0.00270 Hom.: 0

Bravo AF: 0.00253

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Hereditary spastic paraplegia 35 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	2.5
DANN	Benign	0.72
PhyloP100		0.45

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

Other links and lift over

dbSNP: rs573058036; hg19: chr16-74747267;