15-80153021-C-T

Position:

chr15-80153021-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001374377.1(FAH):c.-29-5C>T variant causes a splice region, intron 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. 3/3 splice prediction tools predict no significant impact on normal splicing. 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_001374377.1 splice_region, intron

Scores

Splicing: ADA: 0.00005510

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 0.0910

Variant links:

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 links:

FAH (HGNC:):

FAH links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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 GnomAd4 at 15 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	#exon/exons	MANE	Protein	UniProt
FAH	NM_000137.4 linkuse as main transcript	c.-34C>T	5_prime_UTR_variant	1/14	ENST00000561421.6	NP_000128.1	P16930-1A0A384P5L6
FAH	NM_001374377.1 linkuse as main transcript	c.-29-5C>T	splice_region_variant, intron_variant			NP_001361306.1
FAH	NM_001374380.1 linkuse as main transcript	c.-29-5C>T	splice_region_variant, intron_variant			NP_001361309.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FAH	ENST00000561421 linkuse as main transcript	c.-34C>T		5_prime_UTR_variant	1/14	1	NM_000137.4	ENSP00000453347.2		P16930-1

Frequencies

GnomAD3 genomes

AF:

0.0111

AC:

1689

AN:

152172

Hom.:

Cov.:

show subpopulations

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.:

AF XY:

0.0113

AC XY:

1508

AN XY:

133712

show subpopulations

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.:

AF XY:

0.0160

AC XY:

11564

AN XY:

721658

show subpopulations

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.:

Cov.:

AF XY:

0.0107

AC XY:

796

AN XY:

74464

show subpopulations

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.:

Bravo

AF:

0.00911

Asia WGS

AF:

0.00115

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

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. -

not provided

Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.73

CADD

Benign

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over