rs1057517084

Positions:

• chr15-80172150-CT-C
• chr15-80172150-CT-CTT

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000137.4(FAH):​c.615del​(p.Phe205LeufsTer2) variant causes a frameshift, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,460,500 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: FAH NM_000137.4 frameshift, splice_region
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 0.108

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]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 15-80172150-CT-C is Pathogenic according to our data. Variant chr15-80172150-CT-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 371201.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FAH	NM_000137.4	c.615del	p.Phe205LeufsTer2	frameshift_variant, splice_region_variant	8/14	ENST00000561421.6
FAH	NM_001374377.1	c.615del	p.Phe205LeufsTer2	frameshift_variant, splice_region_variant	9/15
FAH	NM_001374380.1	c.615del	p.Phe205LeufsTer2	frameshift_variant, splice_region_variant	9/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FAH	ENST00000561421.6	c.615del	p.Phe205LeufsTer2	frameshift_variant, splice_region_variant	8/14	1	NM_000137.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1460500 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 726686

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Tyrosinemia type I Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Jul 26, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Mar 20, 2023	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 371201). This premature translational stop signal has been observed in individual(s) with tyrosinemia type 1 (PMID: 22554029). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Phe205Leufs*2) in the FAH gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in FAH are known to be pathogenic (PMID: 9101289, 9633815). -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 22, 2021	- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs1057517084; hg19: chr15-80464492;