dbSNP rs182356891: 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_001374377.1(FAH):c.-89G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 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_001374377.1 5_prime_UTR

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: 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_benign. The variant received -4 ACMG points.

BP4

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
FAH	NM_001374377.1 link	c.-89G>A	5_prime_UTR_variant	Exon 1 of 15		NP_001361306.1
FAH	NM_001374380.1 link	c.-30+5G>A	splice_region_variant, intron_variant	Intron 1 of 14		NP_001361309.1
FAH	NM_000137.4 link	c.-209G>A	upstream_gene_variant		ENST00000561421.6	NP_000128.1	P16930-1A0A384P5L6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FAH	ENST00000561421.6 link	c.-209G>A		upstream_gene_variant		1	NM_000137.4	ENSP00000453347.2		P16930-1

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

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 = 0.000000), 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 v4.3

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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rs182356891

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over