rs1555441595

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM1PM2PP3_StrongPP5_Moderate

The NM_000137.4(FAH):c.700T>G(p.Trp234Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,457,074 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

FAH
NM_000137.4 missense

Scores

Clinical Significance

Pathogenic criteria provided, single submitter P:1U:1

Conservation

PhyloP100: 7.42

Publications

3 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 10 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 11 uncertain in NM_000137.4

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.989

PP5

Variant 15-80172242-T-G is Pathogenic according to our data. Variant chr15-80172242-T-G is described in ClinVar as Pathogenic. ClinVar VariationId is 554643.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FAH	NM_000137.4 link	c.700T>G	p.Trp234Gly	missense_variant	Exon 8 of 14	ENST00000561421.6	NP_000128.1	P16930-1A0A384P5L6
FAH	NM_001374377.1 link	c.700T>G	p.Trp234Gly	missense_variant	Exon 9 of 15		NP_001361306.1
FAH	NM_001374380.1 link	c.700T>G	p.Trp234Gly	missense_variant	Exon 9 of 15		NP_001361309.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FAH	ENST00000561421.6 link	c.700T>G	p.Trp234Gly	missense_variant	Exon 8 of 14	1	NM_000137.4	ENSP00000453347.2		P16930-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.86e-7

AC:

AN:

1457074

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

725256

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33376

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26102

East Asian (EAS)

AF:

0.00

AC:

AN:

39674

South Asian (SAS)

AF:

0.00

AC:

AN:

86162

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53406

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5758

European-Non Finnish (NFE)

AF:

9.03e-7

AC:

AN:

1107620

Other (OTH)

AF:

0.00

AC:

AN:

60252

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Tyrosinemia type I

Pathogenic:1Uncertain:1

Oct 27, 2017

Counsyl

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Sep 01, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects FAH function (PMID: 7550234, 11278491, 31300554). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt FAH protein function. ClinVar contains an entry for this variant (Variation ID: 554643). This missense change has been observed in individual(s) with tyrosinemia type 1 (PMID: 7550234). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces tryptophan, which is neutral and slightly polar, with glycine, which is neutral and non-polar, at codon 234 of the FAH protein (p.Trp234Gly). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Pathogenic

0.52

BayesDel_noAF

Pathogenic

0.51

CADD

Pathogenic

(source)

DANN

Uncertain

0.98

DEOGEN2

Pathogenic

0.95

D;D;D

Eigen

Pathogenic

0.77

Eigen_PC

Uncertain

0.66

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.98

.;.;D

M_CAP

Pathogenic

0.69

MetaRNN

Pathogenic

0.99

D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.0

M;M;M

PhyloP100

7.4

PrimateAI

Pathogenic

0.83

PROVEAN

Pathogenic

-13

D;D;D

REVEL

Pathogenic

0.94

Sift

Uncertain

0.0010

D;D;D

Sift4G

Uncertain

0.0020

D;D;D

Polyphen

1.0

D;D;D

Vest4

0.89

MutPred

0.89

Gain of disorder (P = 0.0579);Gain of disorder (P = 0.0579);Gain of disorder (P = 0.0579);

MVP

0.96

MPC

1.1

ClinPred

1.0

GERP RS

4.9

Varity_R

0.99

gMVP

0.95

Mutation Taster

=0/100

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.11

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over