rs11554620

Variant names:

• chr16-74716453-A-G
• rs11554620
• NM_024306.5:c.933T>C

Your query was ambiguous. Multiple possible variants found:

• chr16-74716453-A-G
• chr16-74716453-A-C
• chr16-74716453-A-T

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.933T>C​(p.Tyr311Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0388 in 1,613,832 control chromosomes in the GnomAD database, including 2,564 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.077 (952 hom., cov: 31)
  • Exomes 𝑓: 0.035 (1612 hom.)
• Consequence: FA2H NM_024306.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.0720
• Publications: 9 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), ClinGen, G2P

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.69).
• BP6: Variant 16-74716453-A-G is Benign according to our data. Variant chr16-74716453-A-G is described in ClinVar as Benign. ClinVar VariationId is 129033.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.072 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.202 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.933T>C	p.Tyr311Tyr	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.933T>C	p.Tyr311Tyr	synonymous	Exon 6 of 7	ENSP00000219368.3	Q7L5A8-1
	FA2H	ENST00000562145.1	TSL:1	n.654T>C		non_coding_transcript_exon	Exon 1 of 2
	FA2H	ENST00000888352.1		c.927T>C	p.Tyr309Tyr	synonymous	Exon 6 of 7	ENSP00000558411.1

Frequencies

GnomAD3 genomes AF: 0.0771 AC: 11716 AN: 151860 Hom.: 940 Cov.: 31

Gnomad AFR AF: 0.205

Gnomad AMI AF: 0.0263

Gnomad AMR AF: 0.0368

Gnomad ASJ AF: 0.00634

Gnomad EAS AF: 0.0476

Gnomad SAS AF: 0.0193

Gnomad FIN AF: 0.0134

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0301

Gnomad OTH AF: 0.0595

GnomAD2 exomes AF: 0.0377 AC: 9482 AN: 251278 AF XY: 0.0342

Gnomad AFR exome AF: 0.205

Gnomad AMR exome AF: 0.0206

Gnomad ASJ exome AF: 0.00744

Gnomad EAS exome AF: 0.0505

Gnomad FIN exome AF: 0.0113

Gnomad NFE exome AF: 0.0315

Gnomad OTH exome AF: 0.0282

GnomAD4 exome AF: 0.0347 AC: 50785 AN: 1461854 Hom.: 1612 Cov.: 30 AF XY: 0.0337 AC XY: 24504 AN XY: 727224

African (AFR) AF: 0.211 AC: 7073 AN: 33476

American (AMR) AF: 0.0223 AC: 996 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00811 AC: 212 AN: 26134

East Asian (EAS) AF: 0.0409 AC: 1624 AN: 39698

South Asian (SAS) AF: 0.0146 AC: 1262 AN: 86256

European-Finnish (FIN) AF: 0.0126 AC: 675 AN: 53416

Middle Eastern (MID) AF: 0.0305 AC: 176 AN: 5768

European-Non Finnish (NFE) AF: 0.0327 AC: 36344 AN: 1111992

Other (OTH) AF: 0.0401 AC: 2423 AN: 60394

GnomAD4 genome AF: 0.0774 AC: 11765 AN: 151978 Hom.: 952 Cov.: 31 AF XY: 0.0744 AC XY: 5528 AN XY: 74310

African (AFR) AF: 0.205 AC: 8504 AN: 41416

American (AMR) AF: 0.0368 AC: 561 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.00634 AC: 22 AN: 3470

East Asian (EAS) AF: 0.0479 AC: 245 AN: 5112

South Asian (SAS) AF: 0.0189 AC: 91 AN: 4826

European-Finnish (FIN) AF: 0.0134 AC: 142 AN: 10606

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.0301 AC: 2047 AN: 67978

Other (OTH) AF: 0.0579 AC: 122 AN: 2106

Alfa AF: 0.0493 Hom.: 1284

Bravo AF: 0.0847

Asia WGS AF: 0.0500 AC: 174 AN: 3478

EpiCase AF: 0.0269

EpiControl AF: 0.0314

ClinVar

ClinVar submissions

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	-0.69
CADD	Benign	1.5
DANN	Benign	0.57
PhyloP100		-0.072
Mutation Taster		=92/8	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: rs11554620; hg19: chr16-74750351; COSMIC: COSV54726340; COSMIC: COSV54726340;