Genetic Variant FAH:c.-89G>C (chr15-80152846-G-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_001374380.1(FAH):c.-30+5G>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.22 ( 3820 hom., cov: 17)

Exomes 𝑓: 0.27 ( 16380 hom. )

Consequence

FAH
NM_001374380.1 splice_region, intron

Scores

Splicing: ADA: 0.00008294

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

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: Ambry Genetics, Myriad Women’s Health, G2P, Labcorp Genetics (formerly Invitae), Orphanet, ClinGen, Laboratory for Molecular Medicine

FAH links:

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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 15-80152846-G-C is Benign according to our data. Variant chr15-80152846-G-C is described in ClinVar as Benign. ClinVar VariationId is 1258417.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.287 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001374380.1. 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_001374377.1		c.-89G>C	5_prime_UTR	Exon 1 of 15	NP_001361306.1	A0A384P5L6
FAH	NM_001374380.1		c.-30+5G>C	splice_region intron	N/A	NP_001361309.1	A0A384P5L6
FAH	NM_000137.4	MANE Select	c.-209G>C	upstream_gene	N/A	NP_000128.1	A0A384P5L6

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
FAH	ENST00000407106.5	TSL:5	c.-89G>C	5_prime_UTR	Exon 1 of 15	ENSP00000385080.1	P16930-1
FAH	ENST00000874652.1		c.-114G>C	5_prime_UTR	Exon 1 of 15	ENSP00000544711.1
FAH	ENST00000874654.1		c.-72G>C	5_prime_UTR	Exon 1 of 15	ENSP00000544713.1

Frequencies

GnomAD3 genomes

AF:

0.221

AC:

29273

AN:

132498

Hom.:

3825

Cov.:

show subpopulations

Gnomad AFR

AF:

0.102

Gnomad AMI

AF:

0.442

Gnomad AMR

AF:

0.213

Gnomad ASJ

AF:

0.244

Gnomad EAS

AF:

0.135

Gnomad SAS

AF:

0.199

Gnomad FIN

AF:

0.255

Gnomad MID

AF:

0.169

Gnomad NFE

AF:

0.291

Gnomad OTH

AF:

0.217

GnomAD4 exome

AF:

0.269

AC:

114666

AN:

425690

Hom.:

16380

Cov.:

AF XY:

0.268

AC XY:

60393

AN XY:

225562

show subpopulations

African (AFR)

AF:

0.116

AC:

1397

AN:

12022

American (AMR)

AF:

0.218

AC:

4447

AN:

20370

Ashkenazi Jewish (ASJ)

AF:

0.258

AC:

3316

AN:

12836

East Asian (EAS)

AF:

0.156

AC:

4453

AN:

28506

South Asian (SAS)

AF:

0.227

AC:

10820

AN:

47724

European-Finnish (FIN)

AF:

0.286

AC:

7793

AN:

27242

Middle Eastern (MID)

AF:

0.274

AC:

503

AN:

1836

European-Non Finnish (NFE)

AF:

0.301

AC:

75557

AN:

250918

Other (OTH)

AF:

0.263

AC:

6380

AN:

24236

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.519

Heterozygous variant carriers

3538

7076

10614

14152

17690

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

342

684

1026

1368

1710

<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:

0.221

AC:

29278

AN:

132582

Hom.:

3820

Cov.:

AF XY:

0.218

AC XY:

13957

AN XY:

64128

show subpopulations

African (AFR)

AF:

0.102

AC:

3626

AN:

35476

American (AMR)

AF:

0.213

AC:

2892

AN:

13584

Ashkenazi Jewish (ASJ)

AF:

0.244

AC:

790

AN:

3234

East Asian (EAS)

AF:

0.135

AC:

590

AN:

4362

South Asian (SAS)

AF:

0.200

AC:

774

AN:

3862

European-Finnish (FIN)

AF:

0.255

AC:

2207

AN:

8642

Middle Eastern (MID)

AF:

0.143

AC:

AN:

244

European-Non Finnish (NFE)

AF:

0.291

AC:

17659

AN:

60676

Other (OTH)

AF:

0.215

AC:

379

AN:

1764

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.531

Heterozygous variant carriers

992

1984

2975

3967

4959

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

288

576

864

1152

1440

<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:

0.126

Hom.:

289

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.90

CADD

Benign

2.9

(source)

DANN

Benign

0.47

PhyloP100

-0.88

PromoterAI

-0.028

Neutral

(source)

Mutation Taster

=98/2

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000083

dbscSNV1_RF

Benign

0.0060

SpliceAI score (max)

0.010

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