15-80152846-G-C

Variant names:

• chr15-80152846-G-C
• rs182356891
• NM_001374377.1:c.-89G>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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

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

ACMG classification

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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FAH	NM_001374377.1	c.-89G>C		5_prime_UTR_variant	Exon 1 of 15		NP_001361306.1
FAH	NM_001374380.1	c.-30+5G>C		splice_region_variant, intron_variant	Intron 1 of 14		NP_001361309.1
FAH	NM_000137.4	c.-209G>C		upstream_gene_variant		ENST00000561421.6	NP_000128.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FAH	ENST00000561421.6	c.-209G>C		upstream_gene_variant		1	NM_000137.4	ENSP00000453347.2

Frequencies

GnomAD3 genomes AF: 0.221 AC: 29273 AN: 132498 Hom.: 3825 Cov.: 17

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.: 2 AF XY: 0.268 AC XY: 60393 AN XY: 225562

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

GnomAD4 genome AF: 0.221 AC: 29278 AN: 132582 Hom.: 3820 Cov.: 17 AF XY: 0.218 AC XY: 13957 AN XY: 64128

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: 35 AN: 244

European-Non Finnish (NFE) AF: 0.291 AC: 17659 AN: 60676

Other (OTH) AF: 0.215 AC: 379 AN: 1764

Alfa AF: 0.126 Hom.: 289

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 29, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	2.9
DANN	Benign	0.47
PhyloP100		-0.88
PromoterAI		-0.028	Neutral
Mutation Taster		=98/2	polymorphism (auto)

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

Other links and lift over

dbSNP: rs182356891; hg19: chr15-80445188;