15-80159830-G-C

Variant names:

• chr15-80159830-G-C
• rs33929922
• NM_000137.4:c.267G>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000137.4(FAH):​c.267G>C​(p.Leu89Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0797 in 1,614,142 control chromosomes in the GnomAD database, including 5,166 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.075 (431 hom., cov: 34)
  • Exomes 𝑓: 0.080 (4735 hom.)
• Consequence: FAH NM_000137.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 1.56
• Publications: 8 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=-0.64).
• BP6: Variant 15-80159830-G-C is Benign according to our data. Variant chr15-80159830-G-C is described in ClinVar as Benign. ClinVar VariationId is 92444.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.56 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0809 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.267G>C	p.Leu89Leu	synonymous	Exon 3 of 14	NP_000128.1
	FAH	NM_001374377.1		c.267G>C	p.Leu89Leu	synonymous	Exon 4 of 15	NP_001361306.1
	FAH	NM_001374380.1		c.267G>C	p.Leu89Leu	synonymous	Exon 4 of 15	NP_001361309.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FAH	ENST00000561421.6	TSL:1 MANE Select	c.267G>C	p.Leu89Leu	synonymous	Exon 3 of 14	ENSP00000453347.2
	FAH	ENST00000539156.5	TSL:1	n.2295G>C		non_coding_transcript_exon	Exon 2 of 13
	FAH	ENST00000874657.1		c.369G>C	p.Leu123Leu	synonymous	Exon 5 of 16	ENSP00000544716.1

Frequencies

GnomAD3 genomes AF: 0.0745 AC: 11339 AN: 152196 Hom.: 429 Cov.: 34

Gnomad AFR AF: 0.0764

Gnomad AMI AF: 0.139

Gnomad AMR AF: 0.0718

Gnomad ASJ AF: 0.0576

Gnomad EAS AF: 0.0223

Gnomad SAS AF: 0.0881

Gnomad FIN AF: 0.0539

Gnomad MID AF: 0.0759

Gnomad NFE AF: 0.0805

Gnomad OTH AF: 0.0626

GnomAD2 exomes AF: 0.0735 AC: 18492 AN: 251458 AF XY: 0.0738

Gnomad AFR exome AF: 0.0764

Gnomad AMR exome AF: 0.0847

Gnomad ASJ exome AF: 0.0614

Gnomad EAS exome AF: 0.0231

Gnomad FIN exome AF: 0.0541

Gnomad NFE exome AF: 0.0799

Gnomad OTH exome AF: 0.0728

GnomAD4 exome AF: 0.0803 AC: 117372 AN: 1461828 Hom.: 4735 Cov.: 41 AF XY: 0.0803 AC XY: 58421 AN XY: 727214

African (AFR) AF: 0.0759 AC: 2541 AN: 33480

American (AMR) AF: 0.0809 AC: 3617 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0607 AC: 1587 AN: 26136

East Asian (EAS) AF: 0.0295 AC: 1173 AN: 39700

South Asian (SAS) AF: 0.0888 AC: 7659 AN: 86258

European-Finnish (FIN) AF: 0.0538 AC: 2872 AN: 53418

Middle Eastern (MID) AF: 0.0702 AC: 405 AN: 5768

European-Non Finnish (NFE) AF: 0.0837 AC: 93036 AN: 1111954

Other (OTH) AF: 0.0742 AC: 4482 AN: 60392

GnomAD4 genome AF: 0.0745 AC: 11354 AN: 152314 Hom.: 431 Cov.: 34 AF XY: 0.0730 AC XY: 5434 AN XY: 74482

African (AFR) AF: 0.0766 AC: 3186 AN: 41580

American (AMR) AF: 0.0717 AC: 1098 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0576 AC: 200 AN: 3472

East Asian (EAS) AF: 0.0226 AC: 117 AN: 5188

South Asian (SAS) AF: 0.0877 AC: 424 AN: 4832

European-Finnish (FIN) AF: 0.0539 AC: 572 AN: 10604

Middle Eastern (MID) AF: 0.0782 AC: 23 AN: 294

European-Non Finnish (NFE) AF: 0.0805 AC: 5476 AN: 68012

Other (OTH) AF: 0.0620 AC: 131 AN: 2114

Alfa AF: 0.0763 Hom.: 152

Bravo AF: 0.0764

Asia WGS AF: 0.0510 AC: 177 AN: 3478

EpiCase AF: 0.0794

EpiControl AF: 0.0795

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	Tyrosinemia type I (4)
-	-	3	not provided (3)
-	-	3	not specified (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.64
CADD	Benign	3.3
DANN	Benign	0.51
PhyloP100		1.6
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: rs33929922; hg19: chr15-80452172; COSMIC: COSV55723013; COSMIC: COSV55723013;