dbSNP rs1370274: FAH:c.193-23T>C (chr15-80159733-T-C) – 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.193-23T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.604 in 1,613,044 control chromosomes in the GnomAD database, including 296,782 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.60 ( 27377 hom., cov: 32)

Exomes 𝑓: 0.60 ( 269405 hom. )

Consequence

FAH
NM_000137.4 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 0.137

Publications

8 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=-0.9).

BP6

Variant 15-80159733-T-C is Benign according to our data. Variant chr15-80159733-T-C is described in ClinVar as Benign. ClinVar VariationId is 255279.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.761 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.193-23T>C	intron	N/A	NP_000128.1	A0A384P5L6
FAH	NM_001374377.1		c.193-23T>C	intron	N/A	NP_001361306.1	A0A384P5L6
FAH	NM_001374380.1		c.193-23T>C	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.193-23T>C	intron	N/A	ENSP00000453347.2	P16930-1
FAH	ENST00000539156.5	TSL:1	n.2221-23T>C	intron	N/A
FAH	ENST00000874657.1		c.295-23T>C	intron	N/A	ENSP00000544716.1

Frequencies

GnomAD3 genomes

AF:

0.598

AC:

90895

AN:

151952

Hom.:

27368

Cov.:

show subpopulations

Gnomad AFR

AF:

0.611

Gnomad AMI

AF:

0.654

Gnomad AMR

AF:

0.533

Gnomad ASJ

AF:

0.610

Gnomad EAS

AF:

0.781

Gnomad SAS

AF:

0.680

Gnomad FIN

AF:

0.504

Gnomad MID

AF:

0.677

Gnomad NFE

AF:

0.599

Gnomad OTH

AF:

0.600

GnomAD2 exomes

AF:

0.602

AC:

151352

AN:

251466

AF XY:

0.608

show subpopulations

Gnomad AFR exome

AF:

0.612

Gnomad AMR exome

AF:

0.488

Gnomad ASJ exome

AF:

0.617

Gnomad EAS exome

AF:

0.785

Gnomad FIN exome

AF:

0.513

Gnomad NFE exome

AF:

0.597

Gnomad OTH exome

AF:

0.580

GnomAD4 exome

AF:

0.605

AC:

883318

AN:

1460974

Hom.:

269405

Cov.:

AF XY:

0.607

AC XY:

441432

AN XY:

726852

show subpopulations

African (AFR)

AF:

0.608

AC:

20329

AN:

33462

American (AMR)

AF:

0.492

AC:

22008

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.613

AC:

16024

AN:

26128

East Asian (EAS)

AF:

0.799

AC:

31698

AN:

39694

South Asian (SAS)

AF:

0.698

AC:

60228

AN:

86238

European-Finnish (FIN)

AF:

0.517

AC:

27614

AN:

53406

Middle Eastern (MID)

AF:

0.658

AC:

3794

AN:

5764

European-Non Finnish (NFE)

AF:

0.598

AC:

664704

AN:

1111200

Other (OTH)

AF:

0.612

AC:

36919

AN:

60366

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.464

Heterozygous variant carriers

17630

35260

52889

70519

88149

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

18196

36392

54588

72784

90980

<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:

0.598

AC:

90953

AN:

152070

Hom.:

27377

Cov.:

AF XY:

0.594

AC XY:

44198

AN XY:

74354

show subpopulations

African (AFR)

AF:

0.611

AC:

25322

AN:

41474

American (AMR)

AF:

0.532

AC:

8134

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.610

AC:

2117

AN:

3472

East Asian (EAS)

AF:

0.782

AC:

4047

AN:

5178

South Asian (SAS)

AF:

0.679

AC:

3274

AN:

4820

European-Finnish (FIN)

AF:

0.504

AC:

5319

AN:

10562

Middle Eastern (MID)

AF:

0.684

AC:

201

AN:

294

European-Non Finnish (NFE)

AF:

0.599

AC:

40682

AN:

67966

Other (OTH)

AF:

0.598

AC:

1261

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

1905

3810

5714

7619

9524

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

774

1548

2322

3096

3870

<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:

0.604

Hom.:

15790

Bravo

AF:

0.596

Asia WGS

AF:

0.670

AC:

2331

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

not specified (2)

Tyrosinemia type I (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.90

CADD

Benign

7.0

(source)

DANN

Benign

0.81

PhyloP100

0.14

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