rs73481171

chr15-80175033-G-Achr15-80175033-G-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_000137.4(FAH):c.855G>A(p.Pro285=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00159 in 1,610,780 control chromosomes in the GnomAD database, including 50 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. P285P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0087 (24 hom., cov: 32)
  • Exomes 𝑓: 0.00087 (26 hom.)
• Consequence: FAH NM_000137.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -3.62

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.51).
• BP6: Variant 15-80175033-G-A is Benign according to our data. Variant chr15-80175033-G-A is described in ClinVar as [Benign]. Clinvar id is 317215.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.62 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0087 (1296/148982) while in subpopulation AFR AF= 0.0301 (1216/40430). AF 95% confidence interval is 0.0287. There are 24 homozygotes in gnomad4. There are 606 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 24 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FAH	NM_000137.4	c.855G>A	p.Pro285=	synonymous_variant	10/14	ENST00000561421.6
FAH	NM_001374377.1	c.855G>A	p.Pro285=	synonymous_variant	11/15
FAH	NM_001374380.1	c.855G>A	p.Pro285=	synonymous_variant	11/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FAH	ENST00000561421.6	c.855G>A	p.Pro285=	synonymous_variant	10/14	1	NM_000137.4	P1

Frequencies

GnomAD3 genomes AF: 0.00862 AC: 1283 AN: 148860 Hom.: 24 Cov.: 32

Gnomad AFR AF: 0.0298

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00412

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: 0.0000899

Gnomad OTH AF: 0.00597

GnomAD3 exomes AF: 0.00211 AC: 531 AN: 251460 Hom.: 9 AF XY: 0.00138 AC XY: 187 AN XY: 135904

Gnomad AFR exome AF: 0.0292

Gnomad AMR exome AF: 0.00124

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000527

Gnomad OTH exome AF: 0.000814

GnomAD4 exome AF: 0.000869 AC: 1270 AN: 1461798 Hom.: 26 Cov.: 31 AF XY: 0.000747 AC XY: 543 AN XY: 727204

Gnomad4 AFR exome AF: 0.0301

Gnomad4 AMR exome AF: 0.00152

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.000104

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000468

Gnomad4 OTH exome AF: 0.00214

GnomAD4 genome AF: 0.00870 AC: 1296 AN: 148982 Hom.: 24 Cov.: 32 AF XY: 0.00832 AC XY: 606 AN XY: 72860

Gnomad4 AFR AF: 0.0301

Gnomad4 AMR AF: 0.00411

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000899

Gnomad4 OTH AF: 0.00591

Alfa AF: 0.00395 Hom.: 3

Bravo AF: 0.00986

Asia WGS AF: 0.00346 AC: 13 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Tyrosinemia type I Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

May 08, 2018

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
Cadd	Benign	0.054
Dann	Benign	0.58
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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

Other links and lift over

dbSNP: rs73481171; hg19: chr15-80467375;