NM_000137.4:c.81+2T>G

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate

The NM_000137.4(FAH):c.81+2T>G 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 (★).

Frequency

Genomes: 𝑓 0.0 ( 0 hom., cov: 32)

Failed GnomAD Quality Control

Consequence

FAH
NM_000137.4 splice_donor, intron

Scores

Splicing: ADA: 1.000

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 6.31

Publications

0 publications found

Variant links:

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

FAH links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 12 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-G is Pathogenic according to our data. Variant chr15-80153137-T-G is described in CliVar as Likely_pathogenic. Clinvar id is 1522883.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr15-80153137-T-G is described in CliVar as Likely_pathogenic. Clinvar id is 1522883.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr15-80153137-T-G is described in CliVar as Likely_pathogenic. Clinvar id is 1522883.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr15-80153137-T-G is described in CliVar as Likely_pathogenic. Clinvar id is 1522883.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr15-80153137-T-G is described in CliVar as Likely_pathogenic. Clinvar id is 1522883.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr15-80153137-T-G is described in CliVar as Likely_pathogenic. Clinvar id is 1522883.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr15-80153137-T-G is described in CliVar as Likely_pathogenic. Clinvar id is 1522883.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr15-80153137-T-G is described in CliVar as Likely_pathogenic. Clinvar id is 1522883.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr15-80153137-T-G is described in CliVar as Likely_pathogenic. Clinvar id is 1522883.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr15-80153137-T-G is described in CliVar as Likely_pathogenic. Clinvar id is 1522883.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr15-80153137-T-G is described in CliVar as Likely_pathogenic. Clinvar id is 1522883.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr15-80153137-T-G is described in CliVar as Likely_pathogenic. Clinvar id is 1522883.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr15-80153137-T-G is described in CliVar as Likely_pathogenic. Clinvar id is 1522883.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr15-80153137-T-G is described in CliVar as Likely_pathogenic. Clinvar id is 1522883.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr15-80153137-T-G is described in CliVar as Likely_pathogenic. Clinvar id is 1522883.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr15-80153137-T-G is described in CliVar as Likely_pathogenic. Clinvar id is 1522883.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr15-80153137-T-G is described in CliVar as Likely_pathogenic. Clinvar id is 1522883.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr15-80153137-T-G is described in CliVar as Likely_pathogenic. Clinvar id is 1522883.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr15-80153137-T-G is described in CliVar as Likely_pathogenic. Clinvar id is 1522883.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr15-80153137-T-G is described in CliVar as Likely_pathogenic. Clinvar id is 1522883.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr15-80153137-T-G is described in CliVar as Likely_pathogenic. Clinvar id is 1522883.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr15-80153137-T-G is described in CliVar as Likely_pathogenic. Clinvar id is 1522883.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr15-80153137-T-G is described in CliVar as Likely_pathogenic. Clinvar id is 1522883.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr15-80153137-T-G is described in CliVar as Likely_pathogenic. Clinvar id is 1522883.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr15-80153137-T-G is described in CliVar as Likely_pathogenic. Clinvar id is 1522883.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr15-80153137-T-G is described in CliVar as Likely_pathogenic. Clinvar id is 1522883.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
FAH	NM_000137.4 link	c.81+2T>G	splice_donor_variant, intron_variant	Intron 1 of 13	ENST00000561421.6	NP_000128.1	P16930-1A0A384P5L6
FAH	NM_001374377.1 link	c.81+2T>G	splice_donor_variant, intron_variant	Intron 2 of 14		NP_001361306.1
FAH	NM_001374380.1 link	c.81+2T>G	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 link	c.81+2T>G		splice_donor_variant, intron_variant	Intron 1 of 13	1	NM_000137.4	ENSP00000453347.2		P16930-1

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

142386

Hom.:

Cov.:

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

142386

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

69388

African (AFR)

AF:

0.00

AC:

AN:

38214

American (AMR)

AF:

0.00

AC:

AN:

14594

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3354

East Asian (EAS)

AF:

0.00

AC:

AN:

4894

South Asian (SAS)

AF:

0.00

AC:

AN:

4542

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9518

Middle Eastern (MID)

AF:

0.00

AC:

AN:

296

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

64144

Other (OTH)

AF:

0.00

AC:

AN:

1970

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Tyrosinemia type I

Pathogenic:1

Aug 16, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 1522883). This variant has not been reported in the literature in individuals affected with FAH-related conditions. This variant is not present in population databases (gnomAD no frequency). 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). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.62

BayesDel_noAF

Pathogenic

0.15

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

Eigen

Pathogenic

0.94

Eigen_PC

Pathogenic

0.76

FATHMM_MKL

Uncertain

0.91

PhyloP100

6.3

GERP RS

5.1

PromoterAI

-0.28

Neutral

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over