chr15-80180089-C-A

Variant names:

• chr15-80180089-C-A
• rs2043691
• NM_000137.4:c.961-35C>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000137.4(FAH):​c.961-35C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.642 in 1,536,806 control chromosomes in the GnomAD database, including 320,385 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.62 (29395 hom., cov: 32)
  • Exomes 𝑓: 0.64 (290990 hom.)
• Consequence: FAH NM_000137.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.01
• Publications: 11 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=-0.87).
• BP6: Variant 15-80180089-C-A is Benign according to our data. Variant chr15-80180089-C-A is described in ClinVar as Benign. ClinVar VariationId is 255284.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.833 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FAH	NM_000137.4	c.961-35C>A		intron_variant	Intron 11 of 13	ENST00000561421.6	NP_000128.1
FAH	NM_001374377.1	c.961-35C>A		intron_variant	Intron 12 of 14		NP_001361306.1
FAH	NM_001374380.1	c.961-35C>A		intron_variant	Intron 12 of 14		NP_001361309.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FAH	ENST00000561421.6	c.961-35C>A		intron_variant	Intron 11 of 13	1	NM_000137.4	ENSP00000453347.2

Frequencies

GnomAD3 genomes AF: 0.618 AC: 93868 AN: 151892 Hom.: 29378 Cov.: 32

Gnomad AFR AF: 0.547

Gnomad AMI AF: 0.635

Gnomad AMR AF: 0.576

Gnomad ASJ AF: 0.647

Gnomad EAS AF: 0.854

Gnomad SAS AF: 0.729

Gnomad FIN AF: 0.630

Gnomad MID AF: 0.696

Gnomad NFE AF: 0.639

Gnomad OTH AF: 0.657

GnomAD2 exomes AF: 0.646 AC: 154919 AN: 239904 AF XY: 0.656

Gnomad AFR exome AF: 0.539

Gnomad AMR exome AF: 0.506

Gnomad ASJ exome AF: 0.655

Gnomad EAS exome AF: 0.860

Gnomad FIN exome AF: 0.640

Gnomad NFE exome AF: 0.639

Gnomad OTH exome AF: 0.640

GnomAD4 exome AF: 0.645 AC: 893038 AN: 1384796 Hom.: 290990 Cov.: 21 AF XY: 0.649 AC XY: 449597 AN XY: 692990

African (AFR) AF: 0.536 AC: 17158 AN: 32040

American (AMR) AF: 0.518 AC: 22923 AN: 44234

Ashkenazi Jewish (ASJ) AF: 0.650 AC: 16671 AN: 25632

East Asian (EAS) AF: 0.858 AC: 33725 AN: 39324

South Asian (SAS) AF: 0.749 AC: 63515 AN: 84756

European-Finnish (FIN) AF: 0.633 AC: 28125 AN: 44426

Middle Eastern (MID) AF: 0.705 AC: 3968 AN: 5630

European-Non Finnish (NFE) AF: 0.637 AC: 668938 AN: 1050820

Other (OTH) AF: 0.656 AC: 38015 AN: 57934

GnomAD4 genome AF: 0.618 AC: 93931 AN: 152010 Hom.: 29395 Cov.: 32 AF XY: 0.621 AC XY: 46111 AN XY: 74300

African (AFR) AF: 0.548 AC: 22683 AN: 41424

American (AMR) AF: 0.576 AC: 8798 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.647 AC: 2246 AN: 3470

East Asian (EAS) AF: 0.854 AC: 4406 AN: 5160

South Asian (SAS) AF: 0.729 AC: 3519 AN: 4824

European-Finnish (FIN) AF: 0.630 AC: 6658 AN: 10568

Middle Eastern (MID) AF: 0.694 AC: 204 AN: 294

European-Non Finnish (NFE) AF: 0.639 AC: 43459 AN: 67966

Other (OTH) AF: 0.654 AC: 1379 AN: 2110

Alfa AF: 0.601 Hom.: 7545

Bravo AF: 0.605

Asia WGS AF: 0.754 AC: 2621 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Tyrosinemia type I Benign:2

Jul 26, 2019

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 01, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: 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	0.39
DANN	Benign	0.79
PhyloP100		-1.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs2043691; hg19: chr15-80472431; COSMIC: COSV55723901; COSMIC: COSV55723901;