rs11554621

Variant names:

• chr16-74716498-T-C
• rs11554621
• NM_024306.5:c.888A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_024306.5(FA2H):​c.888A>G​(p.Val296Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.145 in 1,613,310 control chromosomes in the GnomAD database, including 18,651 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.15 (2000 hom., cov: 30)
  • Exomes 𝑓: 0.14 (16651 hom.)
• Consequence: FA2H NM_024306.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 1.30
• Publications: 10 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: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.65).
• BP6: Variant 16-74716498-T-C is Benign according to our data. Variant chr16-74716498-T-C is described in ClinVar as Benign. ClinVar VariationId is 129032.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.3 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.217 is higher than 0.05.

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.888A>G	p.Val296Val	synonymous	Exon 6 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.888A>G	p.Val296Val	synonymous	Exon 6 of 7	ENSP00000219368.3	Q7L5A8-1
	FA2H	ENST00000562145.1	TSL:1	n.609A>G		non_coding_transcript_exon	Exon 1 of 2
	FA2H	ENST00000888352.1		c.882A>G	p.Val294Val	synonymous	Exon 6 of 7	ENSP00000558411.1

Frequencies

GnomAD3 genomes AF: 0.153 AC: 23221 AN: 151608 Hom.: 1990 Cov.: 30

Gnomad AFR AF: 0.220

Gnomad AMI AF: 0.135

Gnomad AMR AF: 0.115

Gnomad ASJ AF: 0.105

Gnomad EAS AF: 0.0484

Gnomad SAS AF: 0.0668

Gnomad FIN AF: 0.0586

Gnomad MID AF: 0.0949

Gnomad NFE AF: 0.153

Gnomad OTH AF: 0.158

GnomAD2 exomes AF: 0.116 AC: 29064 AN: 250082 AF XY: 0.115

Gnomad AFR exome AF: 0.217

Gnomad AMR exome AF: 0.0770

Gnomad ASJ exome AF: 0.104

Gnomad EAS exome AF: 0.0508

Gnomad FIN exome AF: 0.0608

Gnomad NFE exome AF: 0.151

Gnomad OTH exome AF: 0.126

GnomAD4 exome AF: 0.145 AC: 211319 AN: 1461584 Hom.: 16651 Cov.: 31 AF XY: 0.142 AC XY: 103185 AN XY: 727086

African (AFR) AF: 0.222 AC: 7430 AN: 33476

American (AMR) AF: 0.0816 AC: 3648 AN: 44680

Ashkenazi Jewish (ASJ) AF: 0.104 AC: 2725 AN: 26130

East Asian (EAS) AF: 0.0410 AC: 1627 AN: 39694

South Asian (SAS) AF: 0.0607 AC: 5235 AN: 86232

European-Finnish (FIN) AF: 0.0631 AC: 3369 AN: 53386

Middle Eastern (MID) AF: 0.128 AC: 738 AN: 5768

European-Non Finnish (NFE) AF: 0.160 AC: 178156 AN: 1111842

Other (OTH) AF: 0.139 AC: 8391 AN: 60376

GnomAD4 genome AF: 0.153 AC: 23268 AN: 151726 Hom.: 2000 Cov.: 30 AF XY: 0.145 AC XY: 10779 AN XY: 74152

African (AFR) AF: 0.220 AC: 9115 AN: 41340

American (AMR) AF: 0.115 AC: 1745 AN: 15232

Ashkenazi Jewish (ASJ) AF: 0.105 AC: 364 AN: 3466

East Asian (EAS) AF: 0.0488 AC: 247 AN: 5066

South Asian (SAS) AF: 0.0666 AC: 320 AN: 4804

European-Finnish (FIN) AF: 0.0586 AC: 619 AN: 10570

Middle Eastern (MID) AF: 0.0918 AC: 27 AN: 294

European-Non Finnish (NFE) AF: 0.153 AC: 10379 AN: 67942

Other (OTH) AF: 0.157 AC: 329 AN: 2100

Alfa AF: 0.155 Hom.: 3456

Bravo AF: 0.162

Asia WGS AF: 0.0900 AC: 313 AN: 3478

EpiCase AF: 0.157

EpiControl AF: 0.157

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Hereditary spastic paraplegia 35 (3)
-	-	3	not specified (3)
-	-	1	Hereditary spastic paraplegia (1)
-	-	1	not provided (1)
-	-	1	Spastic paraplegia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.65
CADD	Benign	9.9
DANN	Benign	0.70
PhyloP100		1.3
Mutation Taster		=95/5	polymorphism (auto)

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: rs11554621; hg19: chr16-74750396; COSMIC: COSV54726348; COSMIC: COSV54726348;