15-80152847-G-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001374380.1(FAH):c.-30+6G>T variant causes a splice donor region, intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0092 (34 hom., cov: 20)
  • Exomes 𝑓: 0.0026 (14 hom.)
• Consequence: FAH NM_001374380.1 splice_donor_region, intron
• Scores: Splicing: ADA: 0.00006129
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.515

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 15-80152847-G-T is Benign according to our data. Variant chr15-80152847-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 1210808.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00923 (1319/142928) while in subpopulation AFR AF= 0.0295 (1104/37402). AF 95% confidence interval is 0.0281. There are 34 homozygotes in gnomad4. There are 615 alleles in male gnomad4 subpopulation. Median coverage is 20. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 33 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FAH	NM_001374377.1	c.-88G>T		5_prime_UTR_variant	1/15
FAH	NM_001374380.1	c.-30+6G>T		splice_donor_region_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FAH	ENST00000407106.5	c.-88G>T		5_prime_UTR_variant	1/15	5		P1
FAH	ENST00000558767.6	c.-208G>T		5_prime_UTR_variant	1/5	2
FAH	ENST00000261755.9	c.-30+6G>T		splice_donor_region_variant, intron_variant		5		P1

Frequencies

GnomAD3 genomes AF: 0.00921 AC: 1316 AN: 142828 Hom.: 33 Cov.: 20

Gnomad AFR AF: 0.0295

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00674

Gnomad ASJ AF: 0.0180

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000612

Gnomad OTH AF: 0.00878

GnomAD4 exome AF: 0.00265 AC: 1116 AN: 421750 Hom.: 14 Cov.: 2 AF XY: 0.00233 AC XY: 522 AN XY: 223608

Gnomad4 AFR exome AF: 0.0385

Gnomad4 AMR exome AF: 0.00446

Gnomad4 ASJ exome AF: 0.0168

Gnomad4 EAS exome AF: 0.0000356

Gnomad4 SAS exome AF: 0.000315

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000721

Gnomad4 OTH exome AF: 0.00606

GnomAD4 genome AF: 0.00923 AC: 1319 AN: 142928 Hom.: 34 Cov.: 20 AF XY: 0.00883 AC XY: 615 AN XY: 69666

Gnomad4 AFR AF: 0.0295

Gnomad4 AMR AF: 0.00673

Gnomad4 ASJ AF: 0.0180

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000612

Gnomad4 OTH AF: 0.00870

Alfa AF: 0.00957 Hom.: 0

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 06, 2020

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
Cadd	Benign	6.8
Dann	Benign	0.73

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000061
dbscSNV1_RF	Benign	0.0
SpliceAI score (max)		0.61		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.61		Position offset: -6

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs542873475; hg19: chr15-80445189;