rs1046371

Variant names:

• chr16-74713126-G-C
• rs1046371
• NM_024306.5:c.*1064C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_024306.5(FA2H):​c.*1064C>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 0.305 in 152,558 control chromosomes in the GnomAD database, including 7,494 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.31 (7459 hom., cov: 33)
  • Exomes 𝑓: 0.37 (35 hom.)
• Consequence: FA2H NM_024306.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.18
• Publications: 7 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 16-74713126-G-C is Benign according to our data. Variant chr16-74713126-G-C is described in ClinVar as Benign. ClinVar VariationId is 320466.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.397 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.*1064C>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.*1064C>G		3_prime_UTR	Exon 7 of 7	ENSP00000219368.3	Q7L5A8-1
	FA2H	ENST00000562145.1	TSL:1	n.1904C>G		non_coding_transcript_exon	Exon 2 of 2
	FA2H	ENST00000888352.1		c.*1064C>G		3_prime_UTR	Exon 7 of 7	ENSP00000558411.1

Frequencies

GnomAD3 genomes AF: 0.305 AC: 46375 AN: 152002 Hom.: 7446 Cov.: 33

Gnomad AFR AF: 0.402

Gnomad AMI AF: 0.207

Gnomad AMR AF: 0.207

Gnomad ASJ AF: 0.264

Gnomad EAS AF: 0.0671

Gnomad SAS AF: 0.266

Gnomad FIN AF: 0.332

Gnomad MID AF: 0.335

Gnomad NFE AF: 0.289

Gnomad OTH AF: 0.283

GnomAD4 exome AF: 0.365 AC: 160 AN: 438 Hom.: 35 Cov.: 0 AF XY: 0.361 AC XY: 96 AN XY: 266

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.367 AC: 157 AN: 428

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.167 AC: 1 AN: 6

Other (OTH) AF: 0.500 AC: 2 AN: 4

GnomAD4 genome AF: 0.305 AC: 46424 AN: 152120 Hom.: 7459 Cov.: 33 AF XY: 0.302 AC XY: 22494 AN XY: 74364

African (AFR) AF: 0.402 AC: 16665 AN: 41470

American (AMR) AF: 0.206 AC: 3155 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.264 AC: 916 AN: 3470

East Asian (EAS) AF: 0.0677 AC: 351 AN: 5188

South Asian (SAS) AF: 0.266 AC: 1282 AN: 4826

European-Finnish (FIN) AF: 0.332 AC: 3514 AN: 10578

Middle Eastern (MID) AF: 0.350 AC: 103 AN: 294

European-Non Finnish (NFE) AF: 0.289 AC: 19657 AN: 67982

Other (OTH) AF: 0.281 AC: 592 AN: 2110

Alfa AF: 0.311 Hom.: 906

Bravo AF: 0.297

Asia WGS AF: 0.199 AC: 694 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	7.2
DANN	Benign	0.29
PhyloP100		2.2
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: rs1046371; hg19: chr16-74747024; COSMIC: COSV54727948; COSMIC: COSV54727948;