16-74713553-C-G

Variant names:

• chr16-74713553-C-G
• rs56033857
• NM_024306.5:c.*637G>C

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.*637G>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.304 in 152,322 control chromosomes in the GnomAD database, including 7,666 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.30 (7655 hom., cov: 33)
  • Exomes 𝑓: 0.36 (11 hom.)
• Consequence: FA2H NM_024306.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.972
• Publications: 4 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=-0.86).
• BP6: Variant 16-74713553-C-G is Benign according to our data. Variant chr16-74713553-C-G is described in ClinVar as Benign. ClinVar VariationId is 320477.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.361 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.*637G>C		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.*637G>C		3_prime_UTR	Exon 7 of 7	ENSP00000219368.3	Q7L5A8-1
	FA2H	ENST00000562145.1	TSL:1	n.1477G>C		non_coding_transcript_exon	Exon 2 of 2
	FA2H	ENST00000888352.1		c.*637G>C		3_prime_UTR	Exon 7 of 7	ENSP00000558411.1

Frequencies

GnomAD3 genomes AF: 0.304 AC: 46262 AN: 152068 Hom.: 7651 Cov.: 33

Gnomad AFR AF: 0.204

Gnomad AMI AF: 0.415

Gnomad AMR AF: 0.354

Gnomad ASJ AF: 0.372

Gnomad EAS AF: 0.0945

Gnomad SAS AF: 0.206

Gnomad FIN AF: 0.343

Gnomad MID AF: 0.347

Gnomad NFE AF: 0.365

Gnomad OTH AF: 0.348

GnomAD4 exome AF: 0.360 AC: 49 AN: 136 Hom.: 11 Cov.: 0 AF XY: 0.345 AC XY: 29 AN XY: 84

African (AFR) AC: 0 AN: 0

American (AMR) AF: 0.00 AC: 0 AN: 2

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: 0.0833 AC: 1 AN: 12

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.377 AC: 43 AN: 114

Other (OTH) AF: 0.625 AC: 5 AN: 8

GnomAD4 genome AF: 0.304 AC: 46290 AN: 152186 Hom.: 7655 Cov.: 33 AF XY: 0.302 AC XY: 22482 AN XY: 74414

African (AFR) AF: 0.204 AC: 8462 AN: 41542

American (AMR) AF: 0.354 AC: 5423 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.372 AC: 1292 AN: 3472

East Asian (EAS) AF: 0.0947 AC: 490 AN: 5172

South Asian (SAS) AF: 0.206 AC: 997 AN: 4830

European-Finnish (FIN) AF: 0.343 AC: 3637 AN: 10594

Middle Eastern (MID) AF: 0.363 AC: 106 AN: 292

European-Non Finnish (NFE) AF: 0.365 AC: 24774 AN: 67966

Other (OTH) AF: 0.346 AC: 731 AN: 2110

Alfa AF: 0.189 Hom.: 406

Bravo AF: 0.305

Asia WGS AF: 0.168 AC: 584 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	-0.86
CADD	Benign	0.82
DANN	Benign	0.46
PhyloP100		-0.97
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: rs56033857; hg19: chr16-74747451;