Genetic Variant FAH:c.-89G>T (chr15-80152846-G-T) – 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>T 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 0.000015 ( 0 hom., cov: 17)

Exomes 𝑓: 0.0000070 ( 0 hom. )

Consequence

FAH
NM_001374380.1 splice_region, intron

Scores

Splicing: ADA: 0.00008294

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=-0.89).

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>T	5_prime_UTR	Exon 1 of 15	NP_001361306.1	A0A384P5L6
FAH	NM_001374380.1		c.-30+5G>T	splice_region intron	N/A	NP_001361309.1	A0A384P5L6
FAH	NM_000137.4	MANE Select	c.-209G>T	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>T	5_prime_UTR	Exon 1 of 15	ENSP00000385080.1	P16930-1
FAH	ENST00000874652.1		c.-114G>T	5_prime_UTR	Exon 1 of 15	ENSP00000544711.1
FAH	ENST00000874654.1		c.-72G>T	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:

0.00000704

AC:

AN:

426168

Hom.:

Cov.:

AF XY:

0.0000133

AC XY:

AN XY:

225806

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:

0.00

AC:

AN:

28540

South Asian (SAS)

AF:

0.0000209

AC:

AN:

47764

European-Finnish (FIN)

AF:

0.00

AC:

AN:

27250

Middle Eastern (MID)

AF:

0.00

AC:

AN:

1840

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

251206

Other (OTH)

AF:

0.0000412

AC:

AN:

24260

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.442

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000151

AC:

AN:

132750

Hom.:

Cov.:

AF XY:

0.0000311

AC XY:

AN XY:

64212

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

35520

American (AMR)

AF:

0.00

AC:

AN:

13604

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3234

East Asian (EAS)

AF:

0.00

AC:

AN:

4366

South Asian (SAS)

AF:

0.00

AC:

AN:

3868

European-Finnish (FIN)

AF:

0.00

AC:

AN:

8650

Middle Eastern (MID)

AF:

0.00

AC:

AN:

244

European-Non Finnish (NFE)

AF:

0.0000165

AC:

AN:

60762

Other (OTH)

AF:

0.000567

AC:

AN:

1764

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.825

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

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

-0.89

CADD

Benign

3.2

(source)

DANN

Benign

0.60

PhyloP100

-0.88

PromoterAI

-0.084

Neutral

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000083

dbscSNV1_RF

Benign

0.0080

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

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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