15-80153021-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000137.4(FAH):c.-34C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0161 in 1,601,178 control chromosomes in the GnomAD database, including 280 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (15 hom., cov: 33)
  • Exomes 𝑓: 0.017 (265 hom.)
• Consequence: FAH NM_000137.4 5_prime_UTR
• Scores: Splicing: ADA: 0.00005510
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.0910

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=-0.73).
• BP6: Variant 15-80153021-C-T is Benign according to our data. Variant chr15-80153021-C-T is described in ClinVar as [Benign]. Clinvar id is 317200.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0111 (1689/152292) while in subpopulation NFE AF= 0.0188 (1276/68000). AF 95% confidence interval is 0.0179. There are 15 homozygotes in gnomad4. There are 796 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 15 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FAH	NM_000137.4	c.-34C>T		5_prime_UTR_variant	1/14	ENST00000561421.6
FAH	NM_001374377.1	c.-29-5C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant
FAH	NM_001374380.1	c.-29-5C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FAH	ENST00000561421.6	c.-34C>T		5_prime_UTR_variant	1/14	1	NM_000137.4	P1

Frequencies

GnomAD3 genomes AF: 0.0111 AC: 1689 AN: 152172 Hom.: 15 Cov.: 33

Gnomad AFR AF: 0.00362

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00294

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0192

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0188

Gnomad OTH AF: 0.00525

GnomAD3 exomes AF: 0.0113 AC: 2776 AN: 246438 Hom.: 34 AF XY: 0.0113 AC XY: 1508 AN XY: 133712

Gnomad AFR exome AF: 0.00304

Gnomad AMR exome AF: 0.00200

Gnomad ASJ exome AF: 0.000796

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.0203

Gnomad NFE exome AF: 0.0196

Gnomad OTH exome AF: 0.0110

GnomAD4 exome AF: 0.0166 AC: 24013 AN: 1448886 Hom.: 265 Cov.: 30 AF XY: 0.0160 AC XY: 11564 AN XY: 721658

Gnomad4 AFR exome AF: 0.00252

Gnomad4 AMR exome AF: 0.00226

Gnomad4 ASJ exome AF: 0.000844

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000105

Gnomad4 FIN exome AF: 0.0199

Gnomad4 NFE exome AF: 0.0201

Gnomad4 OTH exome AF: 0.0101

GnomAD4 genome AF: 0.0111 AC: 1689 AN: 152292 Hom.: 15 Cov.: 33 AF XY: 0.0107 AC XY: 796 AN XY: 74464

Gnomad4 AFR AF: 0.00361

Gnomad4 AMR AF: 0.00294

Gnomad4 ASJ AF: 0.000864

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0192

Gnomad4 NFE AF: 0.0188

Gnomad4 OTH AF: 0.00520

Alfa AF: 0.0113 Hom.: 3

Bravo AF: 0.00911

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Tyrosinemia type I Benign:2

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Aug 16, 2016

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
Cadd	Benign	10
Dann	Benign	0.94

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000055
dbscSNV1_RF	Benign	0.0
SpliceAI score (max)		0.0		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: rs142522569; hg19: chr15-80445363;