16-74713670-C-T

Variant names:

• chr16-74713670-C-T
• rs187456324
• NM_024306.5:c.*520G>A

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.*520G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00494 in 156,930 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 0.0049 (3 hom., cov: 33)
  • Exomes 𝑓: 0.0057 (0 hom.)
• Consequence: FA2H NM_024306.5 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.965
• 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=-0.92).
• BP6: Variant 16-74713670-C-T is Benign according to our data. Variant chr16-74713670-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 320478.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00492 (749/152346) while in subpopulation NFE AF = 0.00753 (512/68028). AF 95% confidence interval is 0.00699. There are 3 homozygotes in GnomAd4. There are 355 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.*520G>A		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.*520G>A		3_prime_UTR	Exon 7 of 7	ENSP00000219368.3	Q7L5A8-1
	FA2H	ENST00000562145.1	TSL:1	n.1360G>A		non_coding_transcript_exon	Exon 2 of 2
	FA2H	ENST00000888352.1		c.*520G>A		3_prime_UTR	Exon 7 of 7	ENSP00000558411.1

Frequencies

GnomAD3 genomes AF: 0.00492 AC: 749 AN: 152228 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.00111

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00700

Gnomad ASJ AF: 0.00634

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.00320

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.00753

Gnomad OTH AF: 0.00860

GnomAD4 exome AF: 0.00567 AC: 26 AN: 4584 Hom.: 0 Cov.: 0 AF XY: 0.00581 AC XY: 14 AN XY: 2408

African (AFR) AF: 0.00 AC: 0 AN: 96

American (AMR) AF: 0.00509 AC: 5 AN: 982

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24

East Asian (EAS) AF: 0.00 AC: 0 AN: 278

South Asian (SAS) AF: 0.00298 AC: 1 AN: 336

European-Finnish (FIN) AF: 0.00943 AC: 3 AN: 318

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 6

European-Non Finnish (NFE) AF: 0.00723 AC: 17 AN: 2352

Other (OTH) AF: 0.00 AC: 0 AN: 192

GnomAD4 genome AF: 0.00492 AC: 749 AN: 152346 Hom.: 3 Cov.: 33 AF XY: 0.00477 AC XY: 355 AN XY: 74496

African (AFR) AF: 0.00111 AC: 46 AN: 41572

American (AMR) AF: 0.00699 AC: 107 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00634 AC: 22 AN: 3472

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

South Asian (SAS) AF: 0.00186 AC: 9 AN: 4830

European-Finnish (FIN) AF: 0.00320 AC: 34 AN: 10630

Middle Eastern (MID) AF: 0.00342 AC: 1 AN: 292

European-Non Finnish (NFE) AF: 0.00753 AC: 512 AN: 68028

Other (OTH) AF: 0.00851 AC: 18 AN: 2116

Alfa AF: 0.00603 Hom.: 0

Bravo AF: 0.00510

Asia WGS AF: 0.00144 AC: 5 AN: 3478

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	-0.92
CADD	Benign	2.1
DANN	Benign	0.68
PhyloP100		-0.96

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: rs187456324; hg19: chr16-74747568;