rs60585303

Variant names:

• chr15-80181163-A-G
• rs60585303
• NM_000137.4:c.1180+4A>G

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_000137.4(FAH):​c.1180+4A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00834 in 1,597,466 control chromosomes in the GnomAD database, including 921 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 0.042 (455 hom., cov: 32)
  • Exomes 𝑓: 0.0048 (466 hom.)
• Consequence: FAH NM_000137.4 splice_region, intron
• Scores: Splicing: ADA: 0.8486
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.731
• 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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.37).
• BP6: Variant 15-80181163-A-G is Benign according to our data. Variant chr15-80181163-A-G is described in ClinVar as Benign. ClinVar VariationId is 255278.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.144 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FAH	NM_000137.4	c.1180+4A>G		splice_region_variant, intron_variant	Intron 13 of 13	ENST00000561421.6	NP_000128.1
FAH	NM_001374377.1	c.1180+4A>G		splice_region_variant, intron_variant	Intron 14 of 14		NP_001361306.1
FAH	NM_001374380.1	c.1180+4A>G		splice_region_variant, intron_variant	Intron 14 of 14		NP_001361309.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FAH	ENST00000561421.6	c.1180+4A>G		splice_region_variant, intron_variant	Intron 13 of 13	1	NM_000137.4	ENSP00000453347.2

Frequencies

GnomAD3 genomes AF: 0.0423 AC: 6436 AN: 152138 Hom.: 453 Cov.: 32

Gnomad AFR AF: 0.147

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0144

Gnomad ASJ AF: 0.00432

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.000632

Gnomad OTH AF: 0.0282

GnomAD2 exomes AF: 0.0118 AC: 2975 AN: 251354 AF XY: 0.00856

Gnomad AFR exome AF: 0.154

Gnomad AMR exome AF: 0.00908

Gnomad ASJ exome AF: 0.00278

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000695

Gnomad OTH exome AF: 0.00798

GnomAD4 exome AF: 0.00475 AC: 6871 AN: 1445210 Hom.: 466 Cov.: 26 AF XY: 0.00411 AC XY: 2956 AN XY: 719940

African (AFR) AF: 0.157 AC: 5220 AN: 33150

American (AMR) AF: 0.0101 AC: 449 AN: 44650

Ashkenazi Jewish (ASJ) AF: 0.00308 AC: 80 AN: 26008

East Asian (EAS) AF: 0.00 AC: 0 AN: 39538

South Asian (SAS) AF: 0.000268 AC: 23 AN: 85852

European-Finnish (FIN) AF: 0.0000188 AC: 1 AN: 53256

Middle Eastern (MID) AF: 0.00995 AC: 57 AN: 5728

European-Non Finnish (NFE) AF: 0.000459 AC: 504 AN: 1097284

Other (OTH) AF: 0.00899 AC: 537 AN: 59744

GnomAD4 genome AF: 0.0424 AC: 6451 AN: 152256 Hom.: 455 Cov.: 32 AF XY: 0.0407 AC XY: 3030 AN XY: 74444

African (AFR) AF: 0.147 AC: 6105 AN: 41526

American (AMR) AF: 0.0144 AC: 220 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00432 AC: 15 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5164

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4826

European-Finnish (FIN) AF: 0.0000941 AC: 1 AN: 10622

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.000632 AC: 43 AN: 68028

Other (OTH) AF: 0.0279 AC: 59 AN: 2114

Alfa AF: 0.0215 Hom.: 117

Bravo AF: 0.0483

Asia WGS AF: 0.00953 AC: 33 AN: 3478

EpiCase AF: 0.00104

EpiControl AF: 0.000771

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Jan 28, 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. -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Tyrosinemia type I Benign:2

Jan 12, 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. -

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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	-0.37
CADD	Benign	17
DANN	Benign	0.91
PhyloP100		0.73
Mutation Taster		=93/7	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.85
dbscSNV1_RF	Benign	0.56
SpliceAI score (max)		0.010		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: rs60585303; hg19: chr15-80473505;