rs80338896

Variant names:

• chr15-80172143-T-G
• rs80338896
• NM_000137.4:c.607-6T>G

Your query was ambiguous. Multiple possible variants found:

• chr15-80172143-T-G
• chr15-80172143-T-C

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PP3 PP5_Moderate

The NM_000137.4(FAH):​c.607-6T>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 0.000000686 in 1,457,404 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: FAH NM_000137.4 splice_region, intron
• Scores: Splicing: ADA: 0.9873
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1 U:1 O:1
• Conservation: PhyloP100: -0.455
• 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: Ambry Genetics, Myriad Women’s Health, G2P, Labcorp Genetics (formerly Invitae), Orphanet, ClinGen, Laboratory for Molecular Medicine

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 15-80172143-T-G is Pathogenic according to our data. Variant chr15-80172143-T-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 21056.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000137.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FAH	NM_000137.4	MANE Select	c.607-6T>G		splice_region intron	N/A	NP_000128.1	A0A384P5L6
	FAH	NM_001374377.1		c.607-6T>G		splice_region intron	N/A	NP_001361306.1	A0A384P5L6
	FAH	NM_001374380.1		c.607-6T>G		splice_region intron	N/A	NP_001361309.1	A0A384P5L6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FAH	ENST00000561421.6	TSL:1 MANE Select	c.607-6T>G		splice_region intron	N/A	ENSP00000453347.2	P16930-1
	FAH	ENST00000539156.5	TSL:1	n.2635-6T>G		splice_region intron	N/A
	FAH	ENST00000874657.1		c.709-6T>G		splice_region intron	N/A	ENSP00000544716.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1457404 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 725390

African (AFR) AF: 0.00 AC: 0 AN: 33408

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26104

East Asian (EAS) AF: 0.00 AC: 0 AN: 39680

South Asian (SAS) AF: 0.00 AC: 0 AN: 86162

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53406

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5668

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1108026

Other (OTH) AF: 0.0000166 AC: 1 AN: 60228

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	1	-	Tyrosinemia type I (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	17
DANN	Benign	0.59
PhyloP100		-0.46
Mutation Taster		=5/95	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.99
dbscSNV1_RF	Pathogenic	0.80
SpliceAI score (max)		0.74		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.36		Position offset: 6
DS_DG_spliceai		0.74		Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs80338896; hg19: chr15-80464485;