Genetic Variant FAH:p.Arg341Trp (chr15-80180184-C-T) – ACMG Classification: Benign (-18 pts)

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBS1BS2

The NM_000137.4(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. R341P) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.016 ( 26 hom., cov: 32)

Exomes 𝑓: 0.019 ( 331 hom. )

Consequence

FAH
NM_000137.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.51

Publications

30 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

FAH links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -18 ACMG points.

PM1

In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_000137.4

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 Benign/Likely_benign|other. ClinVar VariationId is 11868.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 26 AR gene

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
FAH	NM_000137.4	MANE Select	c.1021C>T	p.Arg341Trp	missense	Exon 12 of 14	NP_000128.1
FAH	NM_001374377.1		c.1021C>T	p.Arg341Trp	missense	Exon 13 of 15	NP_001361306.1
FAH	NM_001374380.1		c.1021C>T	p.Arg341Trp	missense	Exon 13 of 15	NP_001361309.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
FAH	ENST00000561421.6	TSL:1 MANE Select	c.1021C>T	p.Arg341Trp	missense	Exon 12 of 14	ENSP00000453347.2
FAH	ENST00000539156.5	TSL:1	n.3049C>T		non_coding_transcript_exon	Exon 11 of 13
FAH	ENST00000874657.1		c.1123C>T	p.Arg375Trp	missense	Exon 14 of 16	ENSP00000544716.1

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

GnomAD2 exomes

AF:

0.0166

AC:

4096

AN:

247378

AF XY:

0.0162

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 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

African (AFR)

AF:

0.00311

AC:

104

AN:

33478

American (AMR)

AF:

0.0136

AC:

610

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.0225

AC:

588

AN:

26132

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39694

South Asian (SAS)

AF:

0.00808

AC:

697

AN:

86258

European-Finnish (FIN)

AF:

0.0266

AC:

1311

AN:

49250

Middle Eastern (MID)

AF:

0.00572

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.0212

AC:

23542

AN:

1111924

Other (OTH)

AF:

0.0176

AC:

1062

AN:

60354

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

1509

3017

4526

6034

7543

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

820

1640

2460

3280

4100

<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:

0.0157

AC:

2383

AN:

152266

Hom.:

Cov.:

AF XY:

0.0154

AC XY:

1143

AN XY:

74458

show subpopulations

African (AFR)

AF:

0.00344

AC:

143

AN:

41564

American (AMR)

AF:

0.0145

AC:

222

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.0190

AC:

AN:

3470

East Asian (EAS)

AF:

0.000386

AC:

AN:

5182

South Asian (SAS)

AF:

0.00559

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.0262

AC:

278

AN:

10608

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0236

AC:

1608

AN:

68002

Other (OTH)

AF:

0.0166

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

120

240

359

479

599

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

150

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0196

Hom.:

147

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

ClinVar submissions as Germline

Significance:Benign/Likely benign; other

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (6)

Tyrosinemia type I (5)

Fumarylacetoacetase pseudodeficiency (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Uncertain

0.021

BayesDel_noAF

Pathogenic

0.28

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.96

Eigen

Uncertain

0.29

Eigen_PC

Benign

0.067

FATHMM_MKL

Benign

0.61

LIST_S2

Pathogenic

0.99

MetaRNN

Benign

0.022

MetaSVM

Uncertain

0.79

MutationAssessor

Pathogenic

3.5

PhyloP100

1.5

PrimateAI

Benign

0.29

PROVEAN

Pathogenic

-5.4

REVEL

Pathogenic

0.83

Sift

Uncertain

0.0010

Sift4G

Pathogenic

0.0010

Polyphen

1.0

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

Mutation Taster

=35/65

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

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