rs80338901

Variant names:

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

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. 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 (★★).

• 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: 26 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: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), Orphanet, G2P, Ambry Genetics, Myriad Women’s Health, ClinGen

ACMG classification

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

• 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 as Germline

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;