NM_000137.4:c.553+33A>G

Variant names:

• chr15-80168182-A-G
• rs1545119
• NM_000137.4:c.553+33A>G

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.553+33A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.728 in 1,610,242 control chromosomes in the GnomAD database, including 428,100 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.73 (40974 hom., cov: 29)
  • Exomes 𝑓: 0.73 (387126 hom.)
• Consequence: FAH NM_000137.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.209
• Publications: 15 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.96).
• BP6: Variant 15-80168182-A-G is Benign according to our data. Variant chr15-80168182-A-G is described in ClinVar as Benign. ClinVar VariationId is 255282.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.854 is higher than 0.05.

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.553+33A>G		intron	N/A	NP_000128.1	A0A384P5L6
	FAH	NM_001374377.1		c.553+33A>G		intron	N/A	NP_001361306.1	A0A384P5L6
	FAH	NM_001374380.1		c.553+33A>G		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.553+33A>G		intron	N/A	ENSP00000453347.2	P16930-1
	FAH	ENST00000539156.5	TSL:1	n.2581+33A>G		intron	N/A
	FAH	ENST00000874657.1		c.655+33A>G		intron	N/A	ENSP00000544716.1

Frequencies

GnomAD3 genomes AF: 0.734 AC: 111294 AN: 151576 Hom.: 40947 Cov.: 29

Gnomad AFR AF: 0.767

Gnomad AMI AF: 0.774

Gnomad AMR AF: 0.666

Gnomad ASJ AF: 0.715

Gnomad EAS AF: 0.876

Gnomad SAS AF: 0.826

Gnomad FIN AF: 0.685

Gnomad MID AF: 0.787

Gnomad NFE AF: 0.720

Gnomad OTH AF: 0.751

GnomAD2 exomes AF: 0.731 AC: 183153 AN: 250622 AF XY: 0.738

Gnomad AFR exome AF: 0.767

Gnomad AMR exome AF: 0.611

Gnomad ASJ exome AF: 0.725

Gnomad EAS exome AF: 0.882

Gnomad FIN exome AF: 0.683

Gnomad NFE exome AF: 0.717

Gnomad OTH exome AF: 0.721

GnomAD4 exome AF: 0.727 AC: 1060366 AN: 1458552 Hom.: 387126 Cov.: 33 AF XY: 0.730 AC XY: 530235 AN XY: 725878

African (AFR) AF: 0.762 AC: 25469 AN: 33438

American (AMR) AF: 0.618 AC: 27634 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.719 AC: 18764 AN: 26106

East Asian (EAS) AF: 0.884 AC: 35102 AN: 39688

South Asian (SAS) AF: 0.841 AC: 72507 AN: 86202

European-Finnish (FIN) AF: 0.682 AC: 35946 AN: 52734

Middle Eastern (MID) AF: 0.789 AC: 4541 AN: 5754

European-Non Finnish (NFE) AF: 0.717 AC: 796043 AN: 1109630

Other (OTH) AF: 0.736 AC: 44360 AN: 60290

GnomAD4 genome AF: 0.734 AC: 111373 AN: 151690 Hom.: 40974 Cov.: 29 AF XY: 0.734 AC XY: 54342 AN XY: 74066

African (AFR) AF: 0.767 AC: 31714 AN: 41354

American (AMR) AF: 0.666 AC: 10149 AN: 15246

Ashkenazi Jewish (ASJ) AF: 0.715 AC: 2476 AN: 3462

East Asian (EAS) AF: 0.876 AC: 4495 AN: 5134

South Asian (SAS) AF: 0.826 AC: 3966 AN: 4804

European-Finnish (FIN) AF: 0.685 AC: 7184 AN: 10480

Middle Eastern (MID) AF: 0.788 AC: 227 AN: 288

European-Non Finnish (NFE) AF: 0.720 AC: 48884 AN: 67908

Other (OTH) AF: 0.748 AC: 1577 AN: 2108

Alfa AF: 0.721 Hom.: 66648

Bravo AF: 0.728

Asia WGS AF: 0.815 AC: 2836 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	Tyrosinemia type I (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	1.6
DANN	Benign	0.47
PhyloP100		0.21
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: rs1545119; hg19: chr15-80460524;