rs2301865

Variant names:

• chr16-74716507-G-A
• rs2301865
• NM_024306.5:c.879C>T

Your query was ambiguous. Multiple possible variants found:

• chr16-74716507-G-A
• chr16-74716507-G-C

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.879C>T​(p.Pro293Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.797 in 1,612,910 control chromosomes in the GnomAD database, including 514,126 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.77 (45600 hom., cov: 29)
  • Exomes 𝑓: 0.80 (468526 hom.)
• Consequence: FA2H NM_024306.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -2.58
• Publications: 20 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), G2P

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP6: Variant 16-74716507-G-A is Benign according to our data. Variant chr16-74716507-G-A is described in ClinVar as Benign. ClinVar VariationId is 129031.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.58 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.809 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.879C>T	p.Pro293Pro	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.879C>T	p.Pro293Pro	synonymous	Exon 6 of 7	ENSP00000219368.3
	FA2H	ENST00000562145.1	TSL:1	n.600C>T		non_coding_transcript_exon	Exon 1 of 2
	FA2H	ENST00000888352.1		c.873C>T	p.Pro291Pro	synonymous	Exon 6 of 7	ENSP00000558411.1

Frequencies

GnomAD3 genomes AF: 0.774 AC: 117281 AN: 151562 Hom.: 45581 Cov.: 29

Gnomad AFR AF: 0.715

Gnomad AMI AF: 0.757

Gnomad AMR AF: 0.770

Gnomad ASJ AF: 0.785

Gnomad EAS AF: 0.665

Gnomad SAS AF: 0.701

Gnomad FIN AF: 0.823

Gnomad MID AF: 0.870

Gnomad NFE AF: 0.815

Gnomad OTH AF: 0.794

GnomAD2 exomes AF: 0.772 AC: 192521 AN: 249406 AF XY: 0.772

Gnomad AFR exome AF: 0.711

Gnomad AMR exome AF: 0.754

Gnomad ASJ exome AF: 0.795

Gnomad EAS exome AF: 0.656

Gnomad FIN exome AF: 0.831

Gnomad NFE exome AF: 0.812

Gnomad OTH exome AF: 0.794

GnomAD4 exome AF: 0.799 AC: 1167962 AN: 1461230 Hom.: 468526 Cov.: 64 AF XY: 0.797 AC XY: 579596 AN XY: 726908

African (AFR) AF: 0.708 AC: 23700 AN: 33468

American (AMR) AF: 0.757 AC: 33742 AN: 44574

Ashkenazi Jewish (ASJ) AF: 0.791 AC: 20678 AN: 26126

East Asian (EAS) AF: 0.652 AC: 25845 AN: 39658

South Asian (SAS) AF: 0.702 AC: 60547 AN: 86202

European-Finnish (FIN) AF: 0.831 AC: 44327 AN: 53336

Middle Eastern (MID) AF: 0.831 AC: 4792 AN: 5766

European-Non Finnish (NFE) AF: 0.815 AC: 906533 AN: 1111728

Other (OTH) AF: 0.792 AC: 47798 AN: 60372

GnomAD4 genome AF: 0.774 AC: 117345 AN: 151680 Hom.: 45600 Cov.: 29 AF XY: 0.772 AC XY: 57233 AN XY: 74098

African (AFR) AF: 0.714 AC: 29506 AN: 41336

American (AMR) AF: 0.770 AC: 11732 AN: 15234

Ashkenazi Jewish (ASJ) AF: 0.785 AC: 2722 AN: 3468

East Asian (EAS) AF: 0.666 AC: 3349 AN: 5030

South Asian (SAS) AF: 0.701 AC: 3377 AN: 4818

European-Finnish (FIN) AF: 0.823 AC: 8683 AN: 10548

Middle Eastern (MID) AF: 0.881 AC: 259 AN: 294

European-Non Finnish (NFE) AF: 0.815 AC: 55359 AN: 67938

Other (OTH) AF: 0.794 AC: 1668 AN: 2102

Alfa AF: 0.802 Hom.: 73886

Bravo AF: 0.768

Asia WGS AF: 0.677 AC: 2357 AN: 3478

EpiCase AF: 0.821

EpiControl AF: 0.818

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	Hereditary spastic paraplegia 35 (5)
-	-	4	not specified (4)
-	-	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	-0.75
CADD	Benign	0.014
DANN	Benign	0.73
PhyloP100		-2.6
Mutation Taster		=100/0	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: rs2301865; hg19: chr16-74750405; COSMIC: COSV54726510; COSMIC: COSV54726510;