chr16-74716339-A-G

Variant names:

• chr16-74716339-A-G
• rs6564160
• NM_024306.5:c.1039+8T>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.1039+8T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0416 in 1,613,220 control chromosomes in the GnomAD database, including 3,509 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.092 (1411 hom., cov: 30)
  • Exomes 𝑓: 0.036 (2098 hom.)
• Consequence: FA2H NM_024306.5 splice_region, intron
• Scores: Splicing: ADA: 0.00001405
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -3.71
• Publications: 6 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 16-74716339-A-G is Benign according to our data. Variant chr16-74716339-A-G is described in ClinVar as Benign. ClinVar VariationId is 129027.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.252 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.1039+8T>C		splice_region intron	N/A	NP_077282.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FA2H	ENST00000219368.8	TSL:1 MANE Select	c.1039+8T>C		splice_region intron	N/A	ENSP00000219368.3
	FA2H	ENST00000562145.1	TSL:1	n.760+8T>C		splice_region intron	N/A
	FA2H	ENST00000888352.1		c.1033+8T>C		splice_region intron	N/A	ENSP00000558411.1

Frequencies

GnomAD3 genomes AF: 0.0918 AC: 13934 AN: 151800 Hom.: 1395 Cov.: 30

Gnomad AFR AF: 0.256

Gnomad AMI AF: 0.0264

Gnomad AMR AF: 0.0433

Gnomad ASJ AF: 0.00634

Gnomad EAS AF: 0.0471

Gnomad SAS AF: 0.0193

Gnomad FIN AF: 0.0131

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.0303

Gnomad OTH AF: 0.0709

GnomAD2 exomes AF: 0.0419 AC: 10490 AN: 250256 AF XY: 0.0373

Gnomad AFR exome AF: 0.262

Gnomad AMR exome AF: 0.0236

Gnomad ASJ exome AF: 0.00738

Gnomad EAS exome AF: 0.0505

Gnomad FIN exome AF: 0.0112

Gnomad NFE exome AF: 0.0316

Gnomad OTH exome AF: 0.0296

GnomAD4 exome AF: 0.0363 AC: 53069 AN: 1461302 Hom.: 2098 Cov.: 30 AF XY: 0.0351 AC XY: 25518 AN XY: 726922

African (AFR) AF: 0.267 AC: 8944 AN: 33450

American (AMR) AF: 0.0255 AC: 1142 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.00812 AC: 212 AN: 26104

East Asian (EAS) AF: 0.0408 AC: 1621 AN: 39698

South Asian (SAS) AF: 0.0147 AC: 1266 AN: 86238

European-Finnish (FIN) AF: 0.0126 AC: 673 AN: 53392

Middle Eastern (MID) AF: 0.0329 AC: 190 AN: 5768

European-Non Finnish (NFE) AF: 0.0327 AC: 36352 AN: 1111560

Other (OTH) AF: 0.0442 AC: 2669 AN: 60382

GnomAD4 genome AF: 0.0921 AC: 13992 AN: 151918 Hom.: 1411 Cov.: 30 AF XY: 0.0886 AC XY: 6581 AN XY: 74282

African (AFR) AF: 0.256 AC: 10598 AN: 41344

American (AMR) AF: 0.0433 AC: 660 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.00634 AC: 22 AN: 3468

East Asian (EAS) AF: 0.0474 AC: 244 AN: 5150

South Asian (SAS) AF: 0.0189 AC: 91 AN: 4816

European-Finnish (FIN) AF: 0.0131 AC: 139 AN: 10596

Middle Eastern (MID) AF: 0.0272 AC: 8 AN: 294

European-Non Finnish (NFE) AF: 0.0303 AC: 2060 AN: 67978

Other (OTH) AF: 0.0692 AC: 146 AN: 2110

Alfa AF: 0.0493 Hom.: 843

Bravo AF: 0.102

Asia WGS AF: 0.0550 AC: 193 AN: 3478

EpiCase AF: 0.0269

EpiControl AF: 0.0313

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	1	Hereditary spastic paraplegia (1)
-	-	1	Hereditary spastic paraplegia 35 (1)
-	-	1	not provided (1)
-	-	1	Spastic paraplegia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.12
DANN	Benign	0.35
PhyloP100		-3.7
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000014
dbscSNV1_RF	Benign	0.0040
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: rs6564160; hg19: chr16-74750237; COSMIC: COSV54726330; COSMIC: COSV54726330;