dbSNP rs1370275: FAH:c.82-13G>A (chr15-80158047-G-A) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000137.4(FAH):c.82-13G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.512 in 1,604,670 control chromosomes in the GnomAD database, including 215,209 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.46 ( 17032 hom., cov: 31)

Exomes 𝑓: 0.52 ( 198177 hom. )

Consequence

FAH
NM_000137.4 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: -4.70

Publications

12 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: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-1.04).

BP6

Variant 15-80158047-G-A is Benign according to our data. Variant chr15-80158047-G-A is described in ClinVar as Benign. ClinVar VariationId is 92446.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.739 is higher than 0.05.

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	Effect	Exon Rank	Protein	UniProt
FAH	NM_000137.4	MANE Select	c.82-13G>A	intron	N/A	NP_000128.1	A0A384P5L6
FAH	NM_001374377.1		c.82-13G>A	intron	N/A	NP_001361306.1	A0A384P5L6
FAH	NM_001374380.1		c.82-13G>A	intron	N/A	NP_001361309.1	A0A384P5L6

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
FAH	ENST00000561421.6	TSL:1 MANE Select	c.82-13G>A	intron	N/A	ENSP00000453347.2	P16930-1
FAH	ENST00000539156.5	TSL:1	n.2097G>A	non_coding_transcript_exon	Exon 1 of 13
FAH	ENST00000874657.1		c.184-13G>A	intron	N/A	ENSP00000544716.1

Frequencies

GnomAD3 genomes

AF:

0.461

AC:

69992

AN:

151768

Hom.:

17037

Cov.:

show subpopulations

Gnomad AFR

AF:

0.318

Gnomad AMI

AF:

0.515

Gnomad AMR

AF:

0.439

Gnomad ASJ

AF:

0.548

Gnomad EAS

AF:

0.758

Gnomad SAS

AF:

0.590

Gnomad FIN

AF:

0.450

Gnomad MID

AF:

0.592

Gnomad NFE

AF:

0.517

Gnomad OTH

AF:

0.492

GnomAD2 exomes

AF:

0.511

AC:

128519

AN:

251430

AF XY:

0.522

show subpopulations

Gnomad AFR exome

AF:

0.312

Gnomad AMR exome

AF:

0.390

Gnomad ASJ exome

AF:

0.553

Gnomad EAS exome

AF:

0.762

Gnomad FIN exome

AF:

0.458

Gnomad NFE exome

AF:

0.516

Gnomad OTH exome

AF:

0.498

GnomAD4 exome

AF:

0.517

AC:

751629

AN:

1452784

Hom.:

198177

Cov.:

AF XY:

0.521

AC XY:

376826

AN XY:

723388

show subpopulations

African (AFR)

AF:

0.301

AC:

10009

AN:

33272

American (AMR)

AF:

0.397

AC:

17759

AN:

44712

Ashkenazi Jewish (ASJ)

AF:

0.550

AC:

14338

AN:

26092

East Asian (EAS)

AF:

0.769

AC:

30482

AN:

39658

South Asian (SAS)

AF:

0.609

AC:

52441

AN:

86088

European-Finnish (FIN)

AF:

0.463

AC:

24740

AN:

53410

Middle Eastern (MID)

AF:

0.579

AC:

3293

AN:

5686

European-Non Finnish (NFE)

AF:

0.514

AC:

567030

AN:

1103776

Other (OTH)

AF:

0.525

AC:

31537

AN:

60090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

17420

34840

52261

69681

87101

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

16344

32688

49032

65376

81720

<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:

0.461

AC:

70017

AN:

151886

Hom.:

17032

Cov.:

AF XY:

0.461

AC XY:

34185

AN XY:

74222

show subpopulations

African (AFR)

AF:

0.318

AC:

13171

AN:

41432

American (AMR)

AF:

0.438

AC:

6686

AN:

15254

Ashkenazi Jewish (ASJ)

AF:

0.548

AC:

1901

AN:

3470

East Asian (EAS)

AF:

0.759

AC:

3901

AN:

5142

South Asian (SAS)

AF:

0.589

AC:

2836

AN:

4812

European-Finnish (FIN)

AF:

0.450

AC:

4744

AN:

10532

Middle Eastern (MID)

AF:

0.592

AC:

174

AN:

294

European-Non Finnish (NFE)

AF:

0.517

AC:

35100

AN:

67930

Other (OTH)

AF:

0.491

AC:

1036

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1844

3687

5531

7374

9218

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

652

1304

1956

2608

3260

<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:

0.508

Hom.:

62893

Bravo

AF:

0.449

Asia WGS

AF:

0.606

AC:

2106

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (5)

Tyrosinemia type I (5)

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-1.0

CADD

Benign

0.0030

(source)

DANN

Benign

0.27

PhyloP100

-4.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over