15-80153021-C-T

Variant names:

• chr15-80153021-C-T
• rs142522569
• NM_000137.4:c.-34C>T

Variant summary

Our verdict is Benign. The variant received -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:4
• Conservation: PhyloP100: 0.0910
• Publications: 3 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=-0.73).
• 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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 15 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FAH	NM_000137.4	c.-34C>T		5_prime_UTR_variant	Exon 1 of 14	ENST00000561421.6	NP_000128.1
FAH	NM_001374377.1	c.-29-5C>T		splice_region_variant, intron_variant	Intron 1 of 14		NP_001361306.1
FAH	NM_001374380.1	c.-29-5C>T		splice_region_variant, intron_variant	Intron 1 of 14		NP_001361309.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FAH	ENST00000561421.6	c.-34C>T		5_prime_UTR_variant	Exon 1 of 14	1	NM_000137.4	ENSP00000453347.2

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

GnomAD2 exomes AF: 0.0113 AC: 2776 AN: 246438 AF XY: 0.0113

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 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

African (AFR) AF: 0.00252 AC: 84 AN: 33296

American (AMR) AF: 0.00226 AC: 101 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.000844 AC: 22 AN: 26078

East Asian (EAS) AF: 0.00 AC: 0 AN: 39656

South Asian (SAS) AF: 0.000105 AC: 9 AN: 86100

European-Finnish (FIN) AF: 0.0199 AC: 982 AN: 49232

Middle Eastern (MID) AF: 0.000348 AC: 2 AN: 5748

European-Non Finnish (NFE) AF: 0.0201 AC: 22207 AN: 1103984

Other (OTH) AF: 0.0101 AC: 606 AN: 60074

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

African (AFR) AF: 0.00361 AC: 150 AN: 41576

American (AMR) AF: 0.00294 AC: 45 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.000864 AC: 3 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.0192 AC: 204 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0188 AC: 1276 AN: 68000

Other (OTH) AF: 0.00520 AC: 11 AN: 2116

Alfa AF: 0.00952 Hom.: 8

Bravo AF: 0.00911

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Tyrosinemia type I Benign:2

Sep 16, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Aug 16, 2016

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	10
DANN	Benign	0.94
PhyloP100		0.091
PromoterAI		0.035	Neutral
Mutation Taster		=97/3	polymorphism

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

Other links and lift over

dbSNP: rs142522569; hg19: chr15-80445363;