chr15-80152846-G-C

Position:

• chr15-80152846-G-C

Variant summary

Our verdict is Benign. Variant got -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 donor 5th base, 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_donor_5th_base, intron
• Scores: Splicing: ADA: 0.00008294
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.875

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]

ACMG classification

Verdict is Benign. Variant got -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/exons	MANE	UniProt
FAH	NM_001374377.1	c.-89G>C		5_prime_UTR_variant	1/15
FAH	NM_001374380.1	c.-30+5G>C		splice_donor_5th_base_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FAH	ENST00000407106.5	c.-89G>C		5_prime_UTR_variant	1/15	5		P1
FAH	ENST00000558767.6	c.-209G>C		5_prime_UTR_variant	1/5	2
FAH	ENST00000261755.9	c.-30+5G>C		splice_donor_5th_base_variant, intron_variant		5		P1

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

Gnomad4 AFR exome AF: 0.116

Gnomad4 AMR exome AF: 0.218

Gnomad4 ASJ exome AF: 0.258

Gnomad4 EAS exome AF: 0.156

Gnomad4 SAS exome AF: 0.227

Gnomad4 FIN exome AF: 0.286

Gnomad4 NFE exome AF: 0.301

Gnomad4 OTH exome AF: 0.263

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

Gnomad4 AFR AF: 0.102

Gnomad4 AMR AF: 0.213

Gnomad4 ASJ AF: 0.244

Gnomad4 EAS AF: 0.135

Gnomad4 SAS AF: 0.200

Gnomad4 FIN AF: 0.255

Gnomad4 NFE AF: 0.291

Gnomad4 OTH AF: 0.215

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

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 29, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	2.9
DANN	Benign	0.47

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

LitVar

Other links and lift over

dbSNP: rs182356891; hg19: chr15-80445188;