Genetic Variant FAH:c.-58G>A (chr15-80152877-G-A) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001374377.1(FAH):c.-58G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.23 ( 4292 hom., cov: 19)

Exomes 𝑓: 0.27 ( 17354 hom. )

Consequence

FAH
NM_001374377.1 5_prime_UTR

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -0.908

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 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.8).

BP6

Variant 15-80152877-G-A is Benign according to our data. Variant chr15-80152877-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 369102.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.292 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
FAH	NM_001374377.1 link	c.-58G>A	5_prime_UTR_variant	Exon 1 of 15		NP_001361306.1
FAH	NM_001374380.1 link	c.-30+36G>A	intron_variant	Intron 1 of 14		NP_001361309.1
FAH	NM_000137.4 link	c.-178G>A	upstream_gene_variant		ENST00000561421.6	NP_000128.1	P16930-1A0A384P5L6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FAH	ENST00000561421.6 link	c.-178G>A		upstream_gene_variant		1	NM_000137.4	ENSP00000453347.2		P16930-1

Frequencies

GnomAD3 genomes

AF:

0.225

AC:

32102

AN:

142456

Hom.:

4297

Cov.:

show subpopulations

Gnomad AFR

AF:

0.105

Gnomad AMI

AF:

0.447

Gnomad AMR

AF:

0.218

Gnomad ASJ

AF:

0.248

Gnomad EAS

AF:

0.136

Gnomad SAS

AF:

0.207

Gnomad FIN

AF:

0.268

Gnomad MID

AF:

0.171

Gnomad NFE

AF:

0.296

Gnomad OTH

AF:

0.228

GnomAD4 exome

AF:

0.269

AC:

123429

AN:

459126

Hom.:

17354

Cov.:

AF XY:

0.267

AC XY:

64912

AN XY:

242774

show subpopulations

Gnomad4 AFR exome

AF:

0.116

Gnomad4 AMR exome

AF:

0.218

Gnomad4 ASJ exome

AF:

0.259

Gnomad4 EAS exome

AF:

0.157

Gnomad4 SAS exome

AF:

0.229

Gnomad4 FIN exome

AF:

0.286

Gnomad4 NFE exome

AF:

0.300

Gnomad4 OTH exome

AF:

0.262

GnomAD4 genome

AF:

0.225

AC:

32114

AN:

142558

Hom.:

4292

Cov.:

AF XY:

0.223

AC XY:

15412

AN XY:

69066

show subpopulations

Gnomad4 AFR

AF:

0.105

Gnomad4 AMR

AF:

0.218

Gnomad4 ASJ

AF:

0.248

Gnomad4 EAS

AF:

0.136

Gnomad4 SAS

AF:

0.208

Gnomad4 FIN

AF:

0.268

Gnomad4 NFE

AF:

0.296

Gnomad4 OTH

AF:

0.226

Alfa

AF:

0.272

Hom.:

817

Bravo

AF:

0.221

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 29, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hypertyrosinemia

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Tyrosinemia type I

Benign:1

Jul 26, 2019

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.80

CADD

Benign

7.2

DANN

Benign

0.56

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.1

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over