Genetic Variant FAH:p.Gln279Leu (chr15-80173143-A-T) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2PM5PP3_Moderate

The NM_000137.4(FAH):c.836A>T(p.Gln279Leu) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q279R) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 33)

Consequence

FAH
NM_000137.4 missense, splice_region

Scores

Splicing: ADA: 0.9848

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 8.52

Publications

13 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: Likely_pathogenic. The variant received 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr15-80173143-A-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 11875.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.906

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.836A>T	p.Gln279Leu	missense splice_region	Exon 9 of 14	NP_000128.1
FAH	NM_001374377.1		c.836A>T	p.Gln279Leu	missense splice_region	Exon 10 of 15	NP_001361306.1
FAH	NM_001374380.1		c.836A>T	p.Gln279Leu	missense splice_region	Exon 10 of 15	NP_001361309.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
FAH	ENST00000561421.6	TSL:1 MANE Select	c.836A>T	p.Gln279Leu	missense splice_region	Exon 9 of 14	ENSP00000453347.2
FAH	ENST00000539156.5	TSL:1	n.2864A>T		splice_region non_coding_transcript_exon	Exon 8 of 13
FAH	ENST00000261755.9	TSL:5	c.836A>T	p.Gln279Leu	missense splice_region	Exon 10 of 15	ENSP00000261755.5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.53

BayesDel_addAF

Pathogenic

0.37

BayesDel_noAF

Pathogenic

0.30

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.92

Eigen

Uncertain

0.59

Eigen_PC

Uncertain

0.49

FATHMM_MKL

Uncertain

0.94

LIST_S2

Pathogenic

0.97

M_CAP

Pathogenic

0.72

MetaRNN

Pathogenic

0.91

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

4.0

PhyloP100

8.5

PrimateAI

Benign

0.45

PROVEAN

Pathogenic

-6.8

REVEL

Pathogenic

0.81

Sift

Uncertain

0.0020

Sift4G

Uncertain

0.0090

Polyphen

1.0

Vest4

0.77

MutPred

0.47

Loss of disorder (P = 0.0618)

MVP

0.87

MPC

0.68

ClinPred

1.0

GERP RS

4.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.7

Varity_R

0.91

gMVP

0.84

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

0.98

dbscSNV1_RF

Benign

0.59

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over