rs73481171

Variant names:

• chr15-80175033-G-A
• rs73481171
• NM_000137.4:c.855G>A

Your query was ambiguous. Multiple possible variants found:

• chr15-80175033-G-A
• chr15-80175033-G-T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_000137.4(FAH):​c.855G>A​(p.Pro285Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00159 in 1,610,780 control chromosomes in the GnomAD database, including 50 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. P285P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0087 (24 hom., cov: 32)
  • Exomes 𝑓: 0.00087 (26 hom.)
• Consequence: FAH NM_000137.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -3.62
• 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.51).
• BP6: Variant 15-80175033-G-A is Benign according to our data. Variant chr15-80175033-G-A is described in ClinVar as Benign. ClinVar VariationId is 317215.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.62 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0087 (1296/148982) while in subpopulation AFR AF = 0.0301 (1216/40430). AF 95% confidence interval is 0.0287. There are 24 homozygotes in GnomAd4. There are 606 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 24 AR gene

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FAH	NM_000137.4	MANE Select	c.855G>A	p.Pro285Pro	synonymous	Exon 10 of 14	NP_000128.1
	FAH	NM_001374377.1		c.855G>A	p.Pro285Pro	synonymous	Exon 11 of 15	NP_001361306.1
	FAH	NM_001374380.1		c.855G>A	p.Pro285Pro	synonymous	Exon 11 of 15	NP_001361309.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FAH	ENST00000561421.6	TSL:1 MANE Select	c.855G>A	p.Pro285Pro	synonymous	Exon 10 of 14	ENSP00000453347.2
	FAH	ENST00000539156.5	TSL:1	n.2883G>A		non_coding_transcript_exon	Exon 9 of 13
	FAH	ENST00000261755.9	TSL:5	c.855G>A	p.Pro285Pro	synonymous	Exon 11 of 15	ENSP00000261755.5

Frequencies

GnomAD3 genomes AF: 0.00862 AC: 1283 AN: 148860 Hom.: 24 Cov.: 32

Gnomad AFR AF: 0.0298

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00412

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000899

Gnomad OTH AF: 0.00597

GnomAD2 exomes AF: 0.00211 AC: 531 AN: 251460 AF XY: 0.00138

Gnomad AFR exome AF: 0.0292

Gnomad AMR exome AF: 0.00124

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000527

Gnomad OTH exome AF: 0.000814

GnomAD4 exome AF: 0.000869 AC: 1270 AN: 1461798 Hom.: 26 Cov.: 31 AF XY: 0.000747 AC XY: 543 AN XY: 727204

African (AFR) AF: 0.0301 AC: 1007 AN: 33478

American (AMR) AF: 0.00152 AC: 68 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39700

South Asian (SAS) AF: 0.000104 AC: 9 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53386

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5768

European-Non Finnish (NFE) AF: 0.0000468 AC: 52 AN: 1111966

Other (OTH) AF: 0.00214 AC: 129 AN: 60396

GnomAD4 genome AF: 0.00870 AC: 1296 AN: 148982 Hom.: 24 Cov.: 32 AF XY: 0.00832 AC XY: 606 AN XY: 72860

African (AFR) AF: 0.0301 AC: 1216 AN: 40430

American (AMR) AF: 0.00411 AC: 62 AN: 15072

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3414

East Asian (EAS) AF: 0.00 AC: 0 AN: 4966

South Asian (SAS) AF: 0.00 AC: 0 AN: 4644

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10526

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 276

European-Non Finnish (NFE) AF: 0.0000899 AC: 6 AN: 66724

Other (OTH) AF: 0.00591 AC: 12 AN: 2030

Alfa AF: 0.00801 Hom.: 8

Bravo AF: 0.00986

Asia WGS AF: 0.00346 AC: 13 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
CADD	Benign	0.054
DANN	Benign	0.58
PhyloP100		-3.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs73481171; hg19: chr15-80467375;