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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FA2H	NM_024306.5	c.879C>T	p.Pro293Pro	synonymous_variant	Exon 6 of 7	ENST00000219368.8	NP_077282.3
FA2H	XM_011523319.3	c.639C>T	p.Pro213Pro	synonymous_variant	Exon 6 of 7		XP_011521621.1
FA2H	XM_011523317.4	c.*1743C>T		3_prime_UTR_variant	Exon 6 of 6		XP_011521619.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FA2H	ENST00000219368.8	c.879C>T	p.Pro293Pro	synonymous_variant	Exon 6 of 7	1	NM_024306.5	ENSP00000219368.3
FA2H	ENST00000562145.1	n.600C>T		non_coding_transcript_exon_variant	Exon 1 of 2	1
FA2H	ENST00000567683.5	n.*158C>T		non_coding_transcript_exon_variant	Exon 4 of 5	2		ENSP00000455126.1
FA2H	ENST00000567683.5	n.*158C>T		3_prime_UTR_variant	Exon 4 of 5	2		ENSP00000455126.1

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

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary spastic paraplegia 35 Benign:5

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Aug 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Sep 21, 2015

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 24, 2015

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not specified Benign:4

Aug 15, 2013

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 22, 2016

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Jul 31, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 95% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy, Progressive Myoclonus Epilepsy and Abnormal Movements and Neurodegeneration with brain iron accumulation. Number of patients: 88. Only high quality variants are reported. -

Spastic paraplegia Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary spastic paraplegia Benign:1

Dec 12, 2016

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

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;