dbSNP rs1370273: FAH:c.314+49G>A (chr15-80159926-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.314+49G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.605 in 1,598,154 control chromosomes in the GnomAD database, including 295,056 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.60 ( 27935 hom., cov: 34)

Exomes 𝑓: 0.61 ( 267121 hom. )

Consequence

FAH
NM_000137.4 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -0.568

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=-0.88).

BP6

Variant 15-80159926-G-A is Benign according to our data. Variant chr15-80159926-G-A is described in ClinVar as Benign. ClinVar VariationId is 255280.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.314+49G>A	intron	N/A	NP_000128.1	A0A384P5L6
FAH	NM_001374377.1		c.314+49G>A	intron	N/A	NP_001361306.1	A0A384P5L6
FAH	NM_001374380.1		c.314+49G>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.314+49G>A	intron	N/A	ENSP00000453347.2	P16930-1
FAH	ENST00000539156.5	TSL:1	n.2342+49G>A	intron	N/A
FAH	ENST00000874657.1		c.416+49G>A	intron	N/A	ENSP00000544716.1

Frequencies

GnomAD3 genomes

AF:

0.604

AC:

91804

AN:

152046

Hom.:

27924

Cov.:

show subpopulations

Gnomad AFR

AF:

0.631

Gnomad AMI

AF:

0.654

Gnomad AMR

AF:

0.534

Gnomad ASJ

AF:

0.610

Gnomad EAS

AF:

0.781

Gnomad SAS

AF:

0.680

Gnomad FIN

AF:

0.505

Gnomad MID

AF:

0.677

Gnomad NFE

AF:

0.598

Gnomad OTH

AF:

0.605

GnomAD2 exomes

AF:

0.605

AC:

137742

AN:

227666

AF XY:

0.611

show subpopulations

Gnomad AFR exome

AF:

0.633

Gnomad AMR exome

AF:

0.491

Gnomad ASJ exome

AF:

0.618

Gnomad EAS exome

AF:

0.786

Gnomad FIN exome

AF:

0.514

Gnomad NFE exome

AF:

0.598

Gnomad OTH exome

AF:

0.582

GnomAD4 exome

AF:

0.605

AC:

875440

AN:

1445990

Hom.:

267121

Cov.:

AF XY:

0.608

AC XY:

436586

AN XY:

718118

show subpopulations

African (AFR)

AF:

0.629

AC:

20895

AN:

33218

American (AMR)

AF:

0.495

AC:

20697

AN:

41846

Ashkenazi Jewish (ASJ)

AF:

0.613

AC:

15873

AN:

25882

East Asian (EAS)

AF:

0.798

AC:

31398

AN:

39336

South Asian (SAS)

AF:

0.698

AC:

59419

AN:

85128

European-Finnish (FIN)

AF:

0.517

AC:

26984

AN:

52180

Middle Eastern (MID)

AF:

0.660

AC:

3499

AN:

5302

European-Non Finnish (NFE)

AF:

0.598

AC:

659933

AN:

1103246

Other (OTH)

AF:

0.614

AC:

36742

AN:

59852

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

15389

30778

46167

61556

76945

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

18130

36260

54390

72520

90650

<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:

0.604

AC:

91867

AN:

152164

Hom.:

27935

Cov.:

AF XY:

0.600

AC XY:

44621

AN XY:

74388

show subpopulations

African (AFR)

AF:

0.631

AC:

26195

AN:

41532

American (AMR)

AF:

0.533

AC:

8161

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.610

AC:

2117

AN:

3470

East Asian (EAS)

AF:

0.781

AC:

4033

AN:

5162

South Asian (SAS)

AF:

0.679

AC:

3276

AN:

4828

European-Finnish (FIN)

AF:

0.505

AC:

5339

AN:

10578

Middle Eastern (MID)

AF:

0.684

AC:

201

AN:

294

European-Non Finnish (NFE)

AF:

0.598

AC:

40675

AN:

67974

Other (OTH)

AF:

0.602

AC:

1274

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1972

3943

5915

7886

9858

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

780

1560

2340

3120

3900

<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:

0.599

Hom.:

67365

Bravo

AF:

0.603

Asia WGS

AF:

0.673

AC:

2339

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

not specified (1)

Tyrosinemia type I (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.88

CADD

Benign

0.15

(source)

DANN

Benign

0.51

PhyloP100

-0.57

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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