rs772895065

chr15-80153137-T-Achr15-80153137-T-Cchr15-80153137-T-G

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PVS1 PM2 PP3_Strong PP5

The NM_000137.4(FAH):c.81+2T>A variant causes a splice donor change. The variant allele was found at a frequency of 0.0000048 in 1,457,870 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: FAH NM_000137.4 splice_donor
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4 U:1
• Conservation: PhyloP100: 6.31

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 15 ACMG points.

• PVS1: Splicing variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 15-80153137-T-A is Pathogenic according to our data. Variant chr15-80153137-T-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 402229.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FAH	NM_000137.4	c.81+2T>A		splice_donor_variant		ENST00000561421.6
FAH	NM_001374377.1	c.81+2T>A		splice_donor_variant
FAH	NM_001374380.1	c.81+2T>A		splice_donor_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FAH	ENST00000561421.6	c.81+2T>A		splice_donor_variant		1	NM_000137.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000120 AC: 3 AN: 250536 Hom.: 0 AF XY: 0.00000738 AC XY: 1 AN XY: 135474

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 SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000265

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000480 AC: 7 AN: 1457870 Hom.: 0 Cov.: 31 AF XY: 0.00000276 AC XY: 2 AN XY: 725364

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: 0.00000631

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Tyrosinemia type I Pathogenic:4 Uncertain:1

Likely pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Jan 31, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Knight Diagnostic Laboratories, Oregon Health and Sciences University	Sep 01, 2015	The c.81+2T>A variant in the FAH gene is a novel variant at the canonical splice site and is predicted to affect the splice donor site in intron 1 leading to abnormal splicing. Splice site variants that result in the absence of the FAH enzyme represent a well-established mechanism of disease in tyrosinemia type 1. This variant has not been reported in the 1000 genomes and Exome Sequencing Project control population databases and has been seen at very low frequency in ExAc (0.003%). In addition, splice-site computational algorithms have predicted this variant to abrogate splicing. While we have provisionally classified this variant as likely pathogenic, splicing studies are necessary to confirm this interpretation. To confirm these findings, we recommend submission of another blood specimen from this individual for RNA analysis. Please note that specific collection criteria are required for this sample. For more details and instructions about sample collection (including a specimen collection kit), please contact our laboratory. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 22, 2023	This sequence change affects a donor splice site in intron 1 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 present in population databases (rs772895065, gnomAD 0.004%). This variant has not been reported in the literature in individuals affected with FAH-related conditions. ClinVar contains an entry for this variant (Variation ID: 402229). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	May 02, 2017	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Baylor Genetics	Sep 30, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.21
Cadd	Pathogenic	33
Dann	Uncertain	0.99
Eigen	Pathogenic	0.94
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Uncertain	0.91	D
MutationTaster	Benign	1.0	D;D;D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		0.98		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.98		Position offset: -2

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

Publications

LitVar

Other links and lift over

dbSNP: rs772895065; hg19: chr15-80445479;