rs2043691

Variant names:

• chr15-80180089-C-A
• rs2043691
• NM_000137.4:c.961-35C>A

Your query was ambiguous. Multiple possible variants found:

• chr15-80180089-C-A
• chr15-80180089-C-T

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.961-35C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.642 in 1,536,806 control chromosomes in the GnomAD database, including 320,385 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.62 (29395 hom., cov: 32)
  • Exomes 𝑓: 0.64 (290990 hom.)
• Consequence: FAH NM_000137.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.01
• Publications: 11 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 15-80180089-C-A is Benign according to our data. Variant chr15-80180089-C-A is described in ClinVar as Benign. ClinVar VariationId is 255284.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.833 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.961-35C>A		intron	N/A	NP_000128.1
	FAH	NM_001374377.1		c.961-35C>A		intron	N/A	NP_001361306.1
	FAH	NM_001374380.1		c.961-35C>A		intron	N/A	NP_001361309.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FAH	ENST00000561421.6	TSL:1 MANE Select	c.961-35C>A		intron	N/A	ENSP00000453347.2
	FAH	ENST00000539156.5	TSL:1	n.2989-35C>A		intron	N/A
	FAH	ENST00000874657.1		c.1063-35C>A		intron	N/A	ENSP00000544716.1

Frequencies

GnomAD3 genomes AF: 0.618 AC: 93868 AN: 151892 Hom.: 29378 Cov.: 32

Gnomad AFR AF: 0.547

Gnomad AMI AF: 0.635

Gnomad AMR AF: 0.576

Gnomad ASJ AF: 0.647

Gnomad EAS AF: 0.854

Gnomad SAS AF: 0.729

Gnomad FIN AF: 0.630

Gnomad MID AF: 0.696

Gnomad NFE AF: 0.639

Gnomad OTH AF: 0.657

GnomAD2 exomes AF: 0.646 AC: 154919 AN: 239904 AF XY: 0.656

Gnomad AFR exome AF: 0.539

Gnomad AMR exome AF: 0.506

Gnomad ASJ exome AF: 0.655

Gnomad EAS exome AF: 0.860

Gnomad FIN exome AF: 0.640

Gnomad NFE exome AF: 0.639

Gnomad OTH exome AF: 0.640

GnomAD4 exome AF: 0.645 AC: 893038 AN: 1384796 Hom.: 290990 Cov.: 21 AF XY: 0.649 AC XY: 449597 AN XY: 692990

African (AFR) AF: 0.536 AC: 17158 AN: 32040

American (AMR) AF: 0.518 AC: 22923 AN: 44234

Ashkenazi Jewish (ASJ) AF: 0.650 AC: 16671 AN: 25632

East Asian (EAS) AF: 0.858 AC: 33725 AN: 39324

South Asian (SAS) AF: 0.749 AC: 63515 AN: 84756

European-Finnish (FIN) AF: 0.633 AC: 28125 AN: 44426

Middle Eastern (MID) AF: 0.705 AC: 3968 AN: 5630

European-Non Finnish (NFE) AF: 0.637 AC: 668938 AN: 1050820

Other (OTH) AF: 0.656 AC: 38015 AN: 57934

GnomAD4 genome AF: 0.618 AC: 93931 AN: 152010 Hom.: 29395 Cov.: 32 AF XY: 0.621 AC XY: 46111 AN XY: 74300

African (AFR) AF: 0.548 AC: 22683 AN: 41424

American (AMR) AF: 0.576 AC: 8798 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.647 AC: 2246 AN: 3470

East Asian (EAS) AF: 0.854 AC: 4406 AN: 5160

South Asian (SAS) AF: 0.729 AC: 3519 AN: 4824

European-Finnish (FIN) AF: 0.630 AC: 6658 AN: 10568

Middle Eastern (MID) AF: 0.694 AC: 204 AN: 294

European-Non Finnish (NFE) AF: 0.639 AC: 43459 AN: 67966

Other (OTH) AF: 0.654 AC: 1379 AN: 2110

Alfa AF: 0.601 Hom.: 7545

Bravo AF: 0.605

Asia WGS AF: 0.754 AC: 2621 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)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.39
DANN	Benign	0.79
PhyloP100		-1.0
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: rs2043691; hg19: chr15-80472431; COSMIC: COSV55723901; COSMIC: COSV55723901;