GeneBe

15-80172150-CT-CTT

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_000137.4(FAH):​c.615dupT​(p.Val206CysfsTer18) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000682 in 1,612,596 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000068 ( 0 hom. )

Consequence

FAH
NM_000137.4 frameshift

Scores

Not classified

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: 0.108

Publications

2 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

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 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-C-CT is Pathogenic according to our data. Variant chr15-80172150-C-CT is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 937956.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
GeneTranscriptTagsHGVScHGVSpEffectExon RankProteinUniProt
FAH
NM_000137.4
MANE Select
c.615dupTp.Val206CysfsTer18
frameshift
Exon 8 of 14NP_000128.1
FAH
NM_001374377.1
c.615dupTp.Val206CysfsTer18
frameshift
Exon 9 of 15NP_001361306.1
FAH
NM_001374380.1
c.615dupTp.Val206CysfsTer18
frameshift
Exon 9 of 15NP_001361309.1

Ensembl Transcripts

Selected
GeneTranscriptTagsHGVScHGVSpEffectExon RankProteinUniProt
FAH
ENST00000561421.6
TSL:1 MANE Select
c.615dupTp.Val206CysfsTer18
frameshift
Exon 8 of 14ENSP00000453347.2
FAH
ENST00000539156.5
TSL:1
n.2643dupT
non_coding_transcript_exon
Exon 7 of 13
FAH
ENST00000261755.9
TSL:5
c.615dupTp.Val206CysfsTer18
frameshift
Exon 9 of 15ENSP00000261755.5

Frequencies

GnomAD3 genomes
AF:
0.00000658
AC:
1
AN:
152070
Hom.:
0
Cov.:
32
show subpopulations
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:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
0.00000685
AC:
10
AN:
1460526
Hom.:
0
Cov.:
31
AF XY:
0.00000550
AC XY:
4
AN XY:
726690
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33454
American (AMR)
AF:
0.00
AC:
0
AN:
44724
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26114
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39692
South Asian (SAS)
AF:
0.0000116
AC:
1
AN:
86230
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53414
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5692
European-Non Finnish (NFE)
AF:
0.00000810
AC:
9
AN:
1110842
Other (OTH)
AF:
0.00
AC:
0
AN:
60364
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.505
Heterozygous variant carriers
0
1
2
2
3
4
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.00000658
AC:
1
AN:
152070
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74298
show subpopulations
⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.
African (AFR)
AF:
0.00
AC:
0
AN:
41406
American (AMR)
AF:
0.00
AC:
0
AN:
15250
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3472
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5186
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4824
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10606
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.0000147
AC:
1
AN:
68018
Other (OTH)
AF:
0.00
AC:
0
AN:
2080
⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.375
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Alfa
AF:
0.00
Hom.:
0
Bravo
AF:
0.00000378

ClinVar

ClinVar submissions as Germline

Significance:Pathogenic/Likely pathogenic
Revision:criteria provided, multiple submitters, no conflicts
View on ClinVar
Pathogenic
VUS
Benign
Condition
2
-
-
Tyrosinemia type I (2)
1
-
-
not provided (1)

Computational scores

Source: dbNSFP v4.9

Name
Calibrated prediction
Score
Prediction
PhyloP100
0.11
Mutation Taster
=3/197
disease causing (ClinVar)

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.18
Details are displayed if max score is > 0.2

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

Publications

Other links and lift over

dbSNP: rs1057517084; hg19: chr15-80464492; API