Genetic Variant FAH:c.-89G>A (chr15-80152846-G-A) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001374380.1(FAH):c.-30+5G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0000075 ( 0 hom., cov: 17)

Exomes 𝑓: 0.0000094 ( 0 hom. )

Consequence

FAH
NM_001374380.1 splice_region, intron

Scores

Splicing: ADA: 0.00006203

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.875

Publications

7 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: Ambry Genetics, Myriad Women’s Health, G2P, Labcorp Genetics (formerly Invitae), Orphanet, ClinGen, Laboratory for Molecular Medicine

FAH links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.88).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001374380.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
FAH	NM_001374377.1		c.-89G>A	5_prime_UTR	Exon 1 of 15	NP_001361306.1	A0A384P5L6
FAH	NM_001374380.1		c.-30+5G>A	splice_region intron	N/A	NP_001361309.1	A0A384P5L6
FAH	NM_000137.4	MANE Select	c.-209G>A	upstream_gene	N/A	NP_000128.1	A0A384P5L6

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
FAH	ENST00000407106.5	TSL:5	c.-89G>A	5_prime_UTR	Exon 1 of 15	ENSP00000385080.1	P16930-1
FAH	ENST00000874652.1		c.-114G>A	5_prime_UTR	Exon 1 of 15	ENSP00000544711.1
FAH	ENST00000874654.1		c.-72G>A	5_prime_UTR	Exon 1 of 15	ENSP00000544713.1

Frequencies

GnomAD3 genomes

AF:

0.00000754

AC:

AN:

132666

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000165

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000939

AC:

AN:

426172

Hom.:

Cov.:

AF XY:

0.00000886

AC XY:

AN XY:

225810

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

12036

American (AMR)

AF:

0.0000490

AC:

AN:

20412

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

12860

East Asian (EAS)

AF:

0.0000701

AC:

AN:

28540

South Asian (SAS)

AF:

0.00

AC:

AN:

47764

European-Finnish (FIN)

AF:

0.00

AC:

AN:

27252

Middle Eastern (MID)

AF:

0.00

AC:

AN:

1840

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

251208

Other (OTH)

AF:

0.0000412

AC:

AN:

24260

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.412

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

AF:

0.00000754

AC:

AN:

132666

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

64110

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

35422

American (AMR)

AF:

0.00

AC:

AN:

13584

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3234

East Asian (EAS)

AF:

0.00

AC:

AN:

4380

South Asian (SAS)

AF:

0.00

AC:

AN:

3880

European-Finnish (FIN)

AF:

0.00

AC:

AN:

8650

Middle Eastern (MID)

AF:

0.00

AC:

AN:

266

European-Non Finnish (NFE)

AF:

0.0000165

AC:

AN:

60768

Other (OTH)

AF:

0.00

AC:

AN:

1744

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

289

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.88

CADD

Benign

3.1

(source)

DANN

Benign

0.70

PhyloP100

-0.88

PromoterAI

-0.097

Neutral

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000062

dbscSNV1_RF

Benign

0.014

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over