chr15-80158171-G-T

Variant names:

• chr15-80158171-G-T
• rs786204683
• NM_000137.4:c.192+1G>T

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1_Moderate PM2 PP5_Very_Strong

The NM_000137.4(FAH):​c.192+1G>T variant causes a splice donor, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000117 in 1,451,764 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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: not found (cov: 32)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: FAH NM_000137.4 splice_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 8.76
• Publications: 1 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: Labcorp Genetics (formerly Invitae), Myriad Women’s Health, Laboratory for Molecular Medicine, G2P, Orphanet, Ambry Genetics, ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.08809524 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 15-80158171-G-T is Pathogenic according to our data. Variant chr15-80158171-G-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 189085.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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FAH	NM_000137.4	MANE Select	c.192+1G>T		splice_donor intron	N/A	NP_000128.1
	FAH	NM_001374377.1		c.192+1G>T		splice_donor intron	N/A	NP_001361306.1
	FAH	NM_001374380.1		c.192+1G>T		splice_donor intron	N/A	NP_001361309.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FAH	ENST00000561421.6	TSL:1 MANE Select	c.192+1G>T		splice_donor intron	N/A	ENSP00000453347.2
	FAH	ENST00000539156.5	TSL:1	n.2220+1G>T		splice_donor intron	N/A
	FAH	ENST00000261755.9	TSL:5	c.192+1G>T		splice_donor intron	N/A	ENSP00000261755.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000117 AC: 17 AN: 1451764 Hom.: 0 Cov.: 29 AF XY: 0.00000968 AC XY: 7 AN XY: 722894

African (AFR) AF: 0.00 AC: 0 AN: 33280

American (AMR) AF: 0.00 AC: 0 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26094

East Asian (EAS) AF: 0.00 AC: 0 AN: 39642

South Asian (SAS) AF: 0.00 AC: 0 AN: 86062

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5750

European-Non Finnish (NFE) AF: 0.0000136 AC: 15 AN: 1102770

Other (OTH) AF: 0.0000167 AC: 1 AN: 60038

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Tyrosinemia type I Pathogenic:5

May 13, 2021

Natera, Inc.

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Nov 01, 2021

Myriad Genetics, Inc.

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

NM_000137.2(FAH):c.192+1G>T is a canonical splice variant classified as likely pathogenic in the context of tyrosinemia type I. c.192+1G>T has been observed in cases with relevant disease (PMID: 9633815). Functional assessments of this variant are not available in the literature. Internal structural analysis of the variant is supportive of pathogenicity. c.192+1G>T has not been observed in population frequency databases. In summary, NM_000137.2(FAH):c.192+1G>T is a canonical splice variant that has internal structural support for pathogenicity and has been observed more frequently in cases with the relevant disease than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.

Feb 24, 2020

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: FAH c.192+1G>T is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes the canonical 5' splicing donor site. One predict the variant weakens the canonical 5' donor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 251492 control chromosomes. c.192+1G>T has been reported as part of a compound heterozygous genotype in the literature in at-least one individual affected with Tyrosinemia Type 1 (example, Bergman_1998). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic.

Mar 26, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects a donor splice site in intron 2 of the FAH gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in FAH are known to be pathogenic (PMID: 9101289, 9633815). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with tyrosinemia type I (PMID: 9633815). ClinVar contains an entry for this variant (Variation ID: 189085). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Uncertain	0.060
CADD	Pathogenic	29
DANN	Uncertain	0.99
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Pathogenic	0.97	D
PhyloP100		8.8
GERP RS		4.5
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.92
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.99		Position offset: -1

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

Other links and lift over

dbSNP: rs786204683; hg19: chr15-80450513;