rs80338901

Variant names:

• chr15-80180230-G-A
• rs80338901
• NM_000137.4:c.1062+5G>A

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PS3 PP3 PP5_Very_Strong

The NM_000137.4(FAH):​c.1062+5G>A variant causes a splice region, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00038 in 1,602,704 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000394056: Functional studies have shown that the variant results in aberrant splicing leading to the skipping of exon 12 of the FAH gene (Arranz et al. 2002" and additional evidence is available in ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00027 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00039 (0 hom.)
• Consequence: FAH NM_000137.4 splice_region, intron
• Scores: Splicing: ADA: 0.9990
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:28 U:1 O:1
• Conservation: PhyloP100: 9.13
• Publications: 27 publications found

Genes affected

FAH (HGNC:3579): (fumarylacetoacetate hydrolase) Predicted to enable fumarylacetoacetase activity. Predicted to be involved in L-phenylalanine catabolic process; homogentisate catabolic process; and tyrosine catabolic process. Predicted to act upstream of or within arginine catabolic process. Located in extracellular exosome. Implicated in tyrosinemia type I. [provided by Alliance of Genome Resources, Apr 2022]

FAH Gene-Disease associations (from GenCC):

• tyrosinemia type I

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Myriad Women’s Health, G2P, Labcorp Genetics (formerly Invitae), Orphanet, ClinGen, Laboratory for Molecular Medicine

ACMG classification

Our verdict: Pathogenic. The variant received 13 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000394056: Functional studies have shown that the variant results in aberrant splicing leading to the skipping of exon 12 of the FAH gene (Arranz et al. 2002; Perez-Carro et al. 2014) and loss of enzyme activity in patient fibroblasts (St-Louis et al. 1995; Bergman et al. 1998).; SCV000695441: Functional studies have shown that this variant leads to aberrant splicing causing either insertion of a 105 base-pair fragment due to a cryptic splice site, or skipping of exon 12, or skipping of both exons 12 and 13 (Hahn_1995, Perez_2014) as well as loss of enzymatic activity in patients cells (Bergeron _2001).; SCV000713107: "In vitro splicing assays provide evidence that the c.1062+5G>A variant impacts splicing (Perez-Carro 2014)."; SCV002073255: Functional analysis found that c.1062+5 G>A results in exon skipping of exon 12 (Pérez-Carro R).; SCV000329344: Functional analysis using a minigene found that c.1062+5 G>A results in exon skipping of exon 12 (Prez-Carro et al. 2014); SCV004113967: Using minigene analysis, the c.1062+5G>A variant was shown to result in exon skipping (Pérez-Carro et al. 2014. PubMed ID: 23895425).; SCV002818245: PS3; SCV006525598: RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Pérez-Carro, 2014; Hahn, 1995).
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 15-80180230-G-A is Pathogenic according to our data. Variant chr15-80180230-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 11870.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000137.4. 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
	FAH	NM_000137.4	MANE Select	c.1062+5G>A		splice_region intron	N/A	NP_000128.1	A0A384P5L6
	FAH	NM_001374377.1		c.1062+5G>A		splice_region intron	N/A	NP_001361306.1	A0A384P5L6
	FAH	NM_001374380.1		c.1062+5G>A		splice_region intron	N/A	NP_001361309.1	A0A384P5L6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FAH	ENST00000561421.6	TSL:1 MANE Select	c.1062+5G>A		splice_region intron	N/A	ENSP00000453347.2	P16930-1
	FAH	ENST00000539156.5	TSL:1	n.3090+5G>A		splice_region intron	N/A
	FAH	ENST00000874657.1		c.1164+5G>A		splice_region intron	N/A	ENSP00000544716.1

Frequencies

GnomAD3 genomes AF: 0.000269 AC: 41 AN: 152180 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000500

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000372 AC: 90 AN: 242110 AF XY: 0.000349

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000706

Gnomad NFE exome AF: 0.000658

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.000392 AC: 568 AN: 1450406 Hom.: 0 Cov.: 31 AF XY: 0.000361 AC XY: 261 AN XY: 722024

African (AFR) AF: 0.0000897 AC: 3 AN: 33438

American (AMR) AF: 0.00 AC: 0 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26122

East Asian (EAS) AF: 0.00 AC: 0 AN: 39686

South Asian (SAS) AF: 0.000197 AC: 17 AN: 86204

European-Finnish (FIN) AF: 0.000502 AC: 22 AN: 43812

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5744

European-Non Finnish (NFE) AF: 0.000462 AC: 513 AN: 1110474

Other (OTH) AF: 0.000199 AC: 12 AN: 60228

GnomAD4 genome AF: 0.000269 AC: 41 AN: 152298 Hom.: 0 Cov.: 32 AF XY: 0.000228 AC XY: 17 AN XY: 74460

African (AFR) AF: 0.0000722 AC: 3 AN: 41564

American (AMR) AF: 0.0000653 AC: 1 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4826

European-Finnish (FIN) AF: 0.000188 AC: 2 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000500 AC: 34 AN: 68010

Other (OTH) AF: 0.00 AC: 0 AN: 2110

Alfa AF: 0.000470 Hom.: 0

Bravo AF: 0.000234

EpiCase AF: 0.000382

EpiControl AF: 0.000474

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
18	-	-	Tyrosinemia type I (19)
7	1	-	not provided (8)
1	-	-	FAH-related disorder (1)
1	-	-	Inborn genetic diseases (1)
1	-	-	Tyrosinemia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.36
CADD	Benign	14
DANN	Uncertain	0.99
PhyloP100		9.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=5/95	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	1.0
SpliceAI score (max)		0.78		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.78		Position offset: -5

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs80338901; hg19: chr15-80472572; COSMIC: COSV55723079;