chr15-80180184-C-T

Position:

chr15-80180184-C-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBS1BS2

The ENST00000561421.6(FAH):c.1021C>T(p.Arg341Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0188 in 1,609,844 control chromosomes in the GnomAD database, including 357 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign,other (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R341Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.016 ( 26 hom., cov: 32)

Exomes 𝑓: 0.019 ( 331 hom. )

Consequence

FAH
ENST00000561421.6 missense

Scores

Clinical Significance

Benign/Likely benign; other criteria provided, multiple submitters, no conflicts P:1B:9O:3

Conservation

PhyloP100: 1.51

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -18 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in ENST00000561421.6

BP4

Computational evidence support a benign effect (MetaRNN=0.02159214).

BP6

Variant 15-80180184-C-T is Benign according to our data. Variant chr15-80180184-C-T is described in ClinVar as [Likely_benign, other]. Clinvar id is 11868.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-80180184-C-T is described in Lovd as [Likely_benign]. Variant chr15-80180184-C-T is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0157 (2383/152266) while in subpopulation NFE AF= 0.0236 (1608/68002). AF 95% confidence interval is 0.0227. There are 26 homozygotes in gnomad4. There are 1143 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 26 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
FAH	NM_000137.4 linkuse as main transcript	c.1021C>T	p.Arg341Trp	missense_variant	12/14	ENST00000561421.6	NP_000128.1
FAH	NM_001374377.1 linkuse as main transcript	c.1021C>T	p.Arg341Trp	missense_variant	13/15		NP_001361306.1
FAH	NM_001374380.1 linkuse as main transcript	c.1021C>T	p.Arg341Trp	missense_variant	13/15		NP_001361309.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FAH	ENST00000561421.6 linkuse as main transcript	c.1021C>T	p.Arg341Trp	missense_variant	12/14	1	NM_000137.4	ENSP00000453347	P1	P16930-1

Frequencies

GnomAD3 genomes

AF:

0.0157

AC:

2385

AN:

152148

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00345

Gnomad AMI

AF:

0.00219

Gnomad AMR

AF:

0.0146

Gnomad ASJ

AF:

0.0190

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.00579

Gnomad FIN

AF:

0.0262

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0236

Gnomad OTH

AF:

0.0167

GnomAD3 exomes

AF:

0.0166

AC:

4096

AN:

247378

Hom.:

AF XY:

0.0162

AC XY:

2175

AN XY:

134200

show subpopulations

Gnomad AFR exome

AF:

0.00384

Gnomad AMR exome

AF:

0.0128

Gnomad ASJ exome

AF:

0.0213

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.00764

Gnomad FIN exome

AF:

0.0277

Gnomad NFE exome

AF:

0.0223

Gnomad OTH exome

AF:

0.0187

GnomAD4 exome

AF:

0.0192

AC:

27949

AN:

1457578

Hom.:

331

Cov.:

AF XY:

0.0190

AC XY:

13773

AN XY:

725322

show subpopulations

Gnomad4 AFR exome

AF:

0.00311

Gnomad4 AMR exome

AF:

0.0136

Gnomad4 ASJ exome

AF:

0.0225

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.00808

Gnomad4 FIN exome

AF:

0.0266

Gnomad4 NFE exome

AF:

0.0212

Gnomad4 OTH exome

AF:

0.0176

GnomAD4 genome

AF:

0.0157

AC:

2383

AN:

152266

Hom.:

Cov.:

AF XY:

0.0154

AC XY:

1143

AN XY:

74458

show subpopulations

Gnomad4 AFR

AF:

0.00344

Gnomad4 AMR

AF:

0.0145

Gnomad4 ASJ

AF:

0.0190

Gnomad4 EAS

AF:

0.000386

Gnomad4 SAS

AF:

0.00559

Gnomad4 FIN

AF:

0.0262

Gnomad4 NFE

AF:

0.0236

Gnomad4 OTH

AF:

0.0166

Alfa

AF:

0.0197

Hom.:

Bravo

AF:

0.0135

TwinsUK

AF:

0.0167

AC:

ALSPAC

AF:

0.0187

AC:

ESP6500AA

AF:

0.00340

AC:

ESP6500EA

AF:

0.0229

AC:

197

ExAC

AF:

0.0166

AC:

2014

Asia WGS

AF:

0.00462

AC:

AN:

3478

EpiCase

AF:

0.0201

EpiControl

AF:

0.0188

ClinVar

Significance: Benign/Likely benign; other

Submissions summary: Pathogenic:1Benign:9Other:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5Other:1

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	FAH: BS1, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
other, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 30, 2018	- Variant classified as "other reportable" ??? variant is clinically benign (not associated with disease) but is reported when observed (e.g. pseudodeficiency alleles).
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 04, 2018	This variant is associated with the following publications: (PMID: 29326876, 27153395, 27535533, 25087612, 25333069, 21228398, 7977370, 11278491) -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Tyrosinemia type I

Benign:3Other:2

other, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 26, 2018	- pseudodeficiency allele
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	May 18, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
not provided, no classification provided	literature only	GeneReviews	-	A single pseudodeficiency allele, c.1021C>T (p.Arg341Trp), leads to decreased FAH enzyme activity and very little immunoreactive protein, but adequate amounts of FAH mRNA [Rootwelt et al 1994]. -

Fumarylacetoacetase pseudodeficiency

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Dec 01, 1994

- -

not specified

Benign:1

Benign, no assertion criteria provided

clinical testing

Genome Diagnostics Laboratory, University Medical Center Utrecht

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Uncertain

0.021

BayesDel_noAF

Pathogenic

0.28

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.96

D;D;D

Eigen

Uncertain

0.29

Eigen_PC

Benign

0.067

FATHMM_MKL

Benign

0.61

LIST_S2

Pathogenic

0.99

.;.;D

MetaRNN

Benign

0.022

T;T;T

MetaSVM

Uncertain

0.79

MutationAssessor

Pathogenic

3.5

H;H;H

MutationTaster

Benign

1.0

A;A;A;A

PrimateAI

Benign

0.29

PROVEAN

Pathogenic

-5.4

D;D;D

REVEL

Pathogenic

0.83

Sift

Uncertain

0.0010

D;D;D

Sift4G

Pathogenic

0.0010

D;D;D

Polyphen

1.0

D;D;D

Vest4

0.21

MPC

0.83

ClinPred

0.93

GERP RS

3.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.72

gMVP

0.79

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