15-80153137-T-C

Variant names:

• chr15-80153137-T-C
• rs772895065
• NM_000137.4:c.81+2T>C

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_000137.4(FAH):​c.81+2T>C variant causes a splice donor, intron change. The variant was absent in control chromosomes in GnomAD project. 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 (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: FAH NM_000137.4 splice_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Likely pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 6.31
• Publications: 0 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 11 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) 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
• PP5: Variant 15-80153137-T-C is Pathogenic according to our data. Variant chr15-80153137-T-C is described in CliVar as Likely_pathogenic. Clinvar id is 370962.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr15-80153137-T-C is described in CliVar as Likely_pathogenic. Clinvar id is 370962.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr15-80153137-T-C is described in CliVar as Likely_pathogenic. Clinvar id is 370962.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr15-80153137-T-C is described in CliVar as Likely_pathogenic. Clinvar id is 370962.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr15-80153137-T-C is described in CliVar as Likely_pathogenic. Clinvar id is 370962.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr15-80153137-T-C is described in CliVar as Likely_pathogenic. Clinvar id is 370962.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr15-80153137-T-C is described in CliVar as Likely_pathogenic. Clinvar id is 370962.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr15-80153137-T-C is described in CliVar as Likely_pathogenic. Clinvar id is 370962.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr15-80153137-T-C is described in CliVar as Likely_pathogenic. Clinvar id is 370962.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr15-80153137-T-C is described in CliVar as Likely_pathogenic. Clinvar id is 370962.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr15-80153137-T-C is described in CliVar as Likely_pathogenic. Clinvar id is 370962.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr15-80153137-T-C is described in CliVar as Likely_pathogenic. Clinvar id is 370962.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr15-80153137-T-C is described in CliVar as Likely_pathogenic. Clinvar id is 370962.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr15-80153137-T-C is described in CliVar as Likely_pathogenic. Clinvar id is 370962.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr15-80153137-T-C is described in CliVar as Likely_pathogenic. Clinvar id is 370962.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr15-80153137-T-C is described in CliVar as Likely_pathogenic. Clinvar id is 370962.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr15-80153137-T-C is described in CliVar as Likely_pathogenic. Clinvar id is 370962.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr15-80153137-T-C is described in CliVar as Likely_pathogenic. Clinvar id is 370962.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr15-80153137-T-C is described in CliVar as Likely_pathogenic. Clinvar id is 370962.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr15-80153137-T-C is described in CliVar as Likely_pathogenic. Clinvar id is 370962.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr15-80153137-T-C is described in CliVar as Likely_pathogenic. Clinvar id is 370962.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr15-80153137-T-C is described in CliVar as Likely_pathogenic. Clinvar id is 370962.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr15-80153137-T-C is described in CliVar as Likely_pathogenic. Clinvar id is 370962.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr15-80153137-T-C is described in CliVar as Likely_pathogenic. Clinvar id is 370962.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr15-80153137-T-C is described in CliVar as Likely_pathogenic. Clinvar id is 370962.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr15-80153137-T-C is described in CliVar as Likely_pathogenic. Clinvar id is 370962.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FAH	NM_000137.4	c.81+2T>C		splice_donor_variant, intron_variant	Intron 1 of 13	ENST00000561421.6	NP_000128.1
FAH	NM_001374377.1	c.81+2T>C		splice_donor_variant, intron_variant	Intron 2 of 14		NP_001361306.1
FAH	NM_001374380.1	c.81+2T>C		splice_donor_variant, intron_variant	Intron 2 of 14		NP_001361309.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FAH	ENST00000561421.6	c.81+2T>C		splice_donor_variant, intron_variant	Intron 1 of 13	1	NM_000137.4	ENSP00000453347.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Tyrosinemia type I Pathogenic:1

May 27, 2016

Counsyl

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Uncertain	0.11
CADD	Pathogenic	30
DANN	Uncertain	0.99
Eigen	Pathogenic	0.94
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Uncertain	0.90	D
PhyloP100		6.3
GERP RS		5.1
PromoterAI		-0.30	Neutral
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	0.86
SpliceAI score (max)		0.93		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.93		Position offset: -2

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

Other links and lift over

dbSNP: rs772895065; hg19: chr15-80445479;