15-80152847-G-T

Variant names:

• chr15-80152847-G-T
• rs542873475
• NM_001374377.1:c.-88G>T

Variant summary

Our verdict is Benign. The variant received -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 region, intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. 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_region, intron
• Scores: Splicing: ADA: 0.00006129
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.515
• Publications: 1 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 -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 the male GnomAd4 subpopulation. Median coverage is 20. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 34 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FAH	NM_001374377.1	c.-88G>T		5_prime_UTR_variant	Exon 1 of 15		NP_001361306.1
FAH	NM_001374380.1	c.-30+6G>T		splice_region_variant, intron_variant	Intron 1 of 14		NP_001361309.1
FAH	NM_000137.4	c.-208G>T		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.-208G>T		upstream_gene_variant		1	NM_000137.4	ENSP00000453347.2

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

African (AFR) AF: 0.0385 AC: 459 AN: 11914

American (AMR) AF: 0.00446 AC: 91 AN: 20398

Ashkenazi Jewish (ASJ) AF: 0.0168 AC: 214 AN: 12716

East Asian (EAS) AF: 0.0000356 AC: 1 AN: 28078

South Asian (SAS) AF: 0.000315 AC: 15 AN: 47684

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 27052

Middle Eastern (MID) AF: 0.00651 AC: 12 AN: 1842

European-Non Finnish (NFE) AF: 0.000721 AC: 179 AN: 248120

Other (OTH) AF: 0.00606 AC: 145 AN: 23946

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

African (AFR) AF: 0.0295 AC: 1104 AN: 37402

American (AMR) AF: 0.00673 AC: 98 AN: 14570

Ashkenazi Jewish (ASJ) AF: 0.0180 AC: 60 AN: 3342

East Asian (EAS) AF: 0.00 AC: 0 AN: 4648

South Asian (SAS) AF: 0.00 AC: 0 AN: 4382

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10110

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 264

European-Non Finnish (NFE) AF: 0.000612 AC: 40 AN: 65384

Other (OTH) AF: 0.00870 AC: 17 AN: 1954

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

Mar 06, 2020

GeneDx

Significance: Likely 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	-0.87
CADD	Benign	6.8
DANN	Benign	0.73
PhyloP100		0.52
PromoterAI		-0.11	Neutral
Mutation Taster		=78/22	polymorphism

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

Other links and lift over

dbSNP: rs542873475; hg19: chr15-80445189;