15-80152695-GCGGGGTCGGGGCAAGGGGAGGGGCGGGGCTCAGGGAGGGAGGAGAGACTGGAGGACCTGAGGCCCA-G

Variant names:

• chr15-80152695-GCGGGGTCGGGGCAAGGGGAGGGGCGGGGCTCAGGGAGGGAGGAGAGACTGGAGGACCTGAGGCCCA-G
• rs1567112643
• ENST00000558022.5:c.-30+151_-30+216delCGGGGTCGGGGCAAGGGGAGGGGCGGGGCTCAGGGAGGGAGGAGAGACTGGAGGACCTGAGGCCCA

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The ENST00000558022.5(FAH):​c.-30+151_-30+216delCGGGGTCGGGGCAAGGGGAGGGGCGGGGCTCAGGGAGGGAGGAGAGACTGGAGGACCTGAGGCCCA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00356 in 102,008 control chromosomes in the GnomAD database, including 4 homozygotes. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.011 (24 hom., cov: 0)
  • Exomes 𝑓: 0.0036 (4 hom.)
  • Failed GnomAD Quality Control
• Consequence: FAH ENST00000558022.5 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.12
• 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: Benign. The variant received -10 ACMG points.

• BP6: Variant 15-80152695-GCGGGGTCGGGGCAAGGGGAGGGGCGGGGCTCAGGGAGGGAGGAGAGACTGGAGGACCTGAGGCCCA-G is Benign according to our data. Variant chr15-80152695-GCGGGGTCGGGGCAAGGGGAGGGGCGGGGCTCAGGGAGGGAGGAGAGACTGGAGGACCTGAGGCCCA-G is described in ClinVar as [Likely_benign]. Clinvar id is 1707388.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAdExome4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0696 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FAH	NM_000137.4	c.-359_-294delCGGGGTCGGGGCAAGGGGAGGGGCGGGGCTCAGGGAGGGAGGAGAGACTGGAGGACCTGAGGCCCA		upstream_gene_variant		ENST00000561421.6	NP_000128.1
FAH	NM_001374377.1	c.-239_-174delCGGGGTCGGGGCAAGGGGAGGGGCGGGGCTCAGGGAGGGAGGAGAGACTGGAGGACCTGAGGCCCA		upstream_gene_variant			NP_001361306.1
FAH	NM_001374380.1	c.-175_-110delCGGGGTCGGGGCAAGGGGAGGGGCGGGGCTCAGGGAGGGAGGAGAGACTGGAGGACCTGAGGCCCA		upstream_gene_variant			NP_001361309.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FAH	ENST00000561421.6	c.-359_-294delCGGGGTCGGGGCAAGGGGAGGGGCGGGGCTCAGGGAGGGAGGAGAGACTGGAGGACCTGAGGCCCA		upstream_gene_variant		1	NM_000137.4	ENSP00000453347.2

Frequencies

GnomAD3 genomes AF: 0.0105 AC: 781 AN: 74302 Hom.: 23 Cov.: 0

Gnomad AFR AF: 0.0370

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00760

Gnomad ASJ AF: 0.0246

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000926

Gnomad OTH AF: 0.00918

GnomAD4 exome AF: 0.00356 AC: 363 AN: 102008 Hom.: 4 AF XY: 0.00312 AC XY: 173 AN XY: 55528

African (AFR) AF: 0.0806 AC: 136 AN: 1688

American (AMR) AF: 0.00992 AC: 40 AN: 4034

Ashkenazi Jewish (ASJ) AF: 0.0323 AC: 75 AN: 2320

East Asian (EAS) AF: 0.00 AC: 0 AN: 2634

South Asian (SAS) AF: 0.000482 AC: 10 AN: 20732

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5050

Middle Eastern (MID) AF: 0.00510 AC: 2 AN: 392

European-Non Finnish (NFE) AF: 0.00105 AC: 63 AN: 59854

Other (OTH) AF: 0.00698 AC: 37 AN: 5304

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0105 AC: 781 AN: 74324 Hom.: 24 Cov.: 0 AF XY: 0.0102 AC XY: 367 AN XY: 35876

African (AFR) AF: 0.0369 AC: 623 AN: 16886

American (AMR) AF: 0.00758 AC: 64 AN: 8438

Ashkenazi Jewish (ASJ) AF: 0.0246 AC: 52 AN: 2114

East Asian (EAS) AF: 0.00 AC: 0 AN: 2610

South Asian (SAS) AF: 0.00 AC: 0 AN: 1762

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5372

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 132

European-Non Finnish (NFE) AF: 0.000926 AC: 33 AN: 35620

Other (OTH) AF: 0.00913 AC: 9 AN: 986

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Apr 25, 2019

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

See Variant Classification Assertion Criteria. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.1

Splicing

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

Other links and lift over

dbSNP: rs1567112643; hg19: chr15-80445037;