dbSNP rs2278204: FAH:c.455+29G>A (chr15-80162365-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.455+29G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0188 in 1,563,212 control chromosomes in the GnomAD database, including 2,490 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.024 ( 293 hom., cov: 33)

Exomes 𝑓: 0.018 ( 2197 hom. )

Consequence

FAH
NM_000137.4 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 0.202

Publications

4 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=-0.81).

BP6

Variant 15-80162365-G-A is Benign according to our data. Variant chr15-80162365-G-A is described in ClinVar as Benign. ClinVar VariationId is 255281.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.244 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.455+29G>A	intron	N/A	NP_000128.1	A0A384P5L6
FAH	NM_001374377.1		c.455+29G>A	intron	N/A	NP_001361306.1	A0A384P5L6
FAH	NM_001374380.1		c.455+29G>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.455+29G>A	intron	N/A	ENSP00000453347.2	P16930-1
FAH	ENST00000539156.5	TSL:1	n.2483+29G>A	intron	N/A
FAH	ENST00000537726.5	TSL:2	c.*23G>A	3_prime_UTR	Exon 6 of 6	ENSP00000507608.1	B7Z4W2

Frequencies

GnomAD3 genomes

AF:

0.0243

AC:

3694

AN:

152198

Hom.:

293

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00511

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0937

Gnomad ASJ

AF:

0.0144

Gnomad EAS

AF:

0.256

Gnomad SAS

AF:

0.0919

Gnomad FIN

AF:

0.00264

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00226

Gnomad OTH

AF:

0.0239

GnomAD2 exomes

AF:

0.0533

AC:

13412

AN:

251420

AF XY:

0.0496

show subpopulations

Gnomad AFR exome

AF:

0.00480

Gnomad AMR exome

AF:

0.156

Gnomad ASJ exome

AF:

0.0139

Gnomad EAS exome

AF:

0.265

Gnomad FIN exome

AF:

0.00217

Gnomad NFE exome

AF:

0.00147

Gnomad OTH exome

AF:

0.0285

GnomAD4 exome

AF:

0.0182

AC:

25651

AN:

1410896

Hom.:

2197

Cov.:

AF XY:

0.0191

AC XY:

13495

AN XY:

705038

show subpopulations

African (AFR)

AF:

0.00275

AC:

AN:

32342

American (AMR)

AF:

0.149

AC:

6633

AN:

44646

Ashkenazi Jewish (ASJ)

AF:

0.0119

AC:

306

AN:

25804

East Asian (EAS)

AF:

0.230

AC:

9084

AN:

39434

South Asian (SAS)

AF:

0.0774

AC:

6598

AN:

85280

European-Finnish (FIN)

AF:

0.00213

AC:

114

AN:

53400

Middle Eastern (MID)

AF:

0.00600

AC:

AN:

5664

European-Non Finnish (NFE)

AF:

0.00104

AC:

1103

AN:

1065574

Other (OTH)

AF:

0.0288

AC:

1690

AN:

58752

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

1177

2354

3532

4709

5886

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

354

708

1062

1416

1770

<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:

0.0243

AC:

3700

AN:

152316

Hom.:

293

Cov.:

AF XY:

0.0275

AC XY:

2046

AN XY:

74472

show subpopulations

African (AFR)

AF:

0.00510

AC:

212

AN:

41582

American (AMR)

AF:

0.0941

AC:

1440

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.0144

AC:

AN:

3470

East Asian (EAS)

AF:

0.256

AC:

1322

AN:

5170

South Asian (SAS)

AF:

0.0916

AC:

442

AN:

4826

European-Finnish (FIN)

AF:

0.00264

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00226

AC:

154

AN:

68026

Other (OTH)

AF:

0.0246

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

158

316

474

632

790

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

144

192

240

<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:

0.0185

Hom.:

Bravo

AF:

0.0302

Asia WGS

AF:

0.158

AC:

550

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (2)

not provided (1)

Tyrosinemia type I (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.81

CADD

Benign

(source)

DANN

Benign

0.57

PhyloP100

0.20

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.080

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