rs1370273

Variant names:

• chr15-80159926-G-A
• rs1370273
• NM_000137.4:c.314+49G>A

Your query was ambiguous. Multiple possible variants found:

• chr15-80159926-G-A
• chr15-80159926-G-C
• chr15-80159926-G-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.314+49G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.605 in 1,598,154 control chromosomes in the GnomAD database, including 295,056 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.60 (27935 hom., cov: 34)
  • Exomes 𝑓: 0.61 (267121 hom.)
• Consequence: FAH NM_000137.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.568
• Publications: 12 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=-0.88).
• BP6: Variant 15-80159926-G-A is Benign according to our data. Variant chr15-80159926-G-A is described in ClinVar as Benign. ClinVar VariationId is 255280.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.761 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FAH	NM_000137.4	c.314+49G>A		intron_variant	Intron 3 of 13	ENST00000561421.6	NP_000128.1
FAH	NM_001374377.1	c.314+49G>A		intron_variant	Intron 4 of 14		NP_001361306.1
FAH	NM_001374380.1	c.314+49G>A		intron_variant	Intron 4 of 14		NP_001361309.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FAH	ENST00000561421.6	c.314+49G>A		intron_variant	Intron 3 of 13	1	NM_000137.4	ENSP00000453347.2

Frequencies

GnomAD3 genomes AF: 0.604 AC: 91804 AN: 152046 Hom.: 27924 Cov.: 34

Gnomad AFR AF: 0.631

Gnomad AMI AF: 0.654

Gnomad AMR AF: 0.534

Gnomad ASJ AF: 0.610

Gnomad EAS AF: 0.781

Gnomad SAS AF: 0.680

Gnomad FIN AF: 0.505

Gnomad MID AF: 0.677

Gnomad NFE AF: 0.598

Gnomad OTH AF: 0.605

GnomAD2 exomes AF: 0.605 AC: 137742 AN: 227666 AF XY: 0.611

Gnomad AFR exome AF: 0.633

Gnomad AMR exome AF: 0.491

Gnomad ASJ exome AF: 0.618

Gnomad EAS exome AF: 0.786

Gnomad FIN exome AF: 0.514

Gnomad NFE exome AF: 0.598

Gnomad OTH exome AF: 0.582

GnomAD4 exome AF: 0.605 AC: 875440 AN: 1445990 Hom.: 267121 Cov.: 34 AF XY: 0.608 AC XY: 436586 AN XY: 718118

African (AFR) AF: 0.629 AC: 20895 AN: 33218

American (AMR) AF: 0.495 AC: 20697 AN: 41846

Ashkenazi Jewish (ASJ) AF: 0.613 AC: 15873 AN: 25882

East Asian (EAS) AF: 0.798 AC: 31398 AN: 39336

South Asian (SAS) AF: 0.698 AC: 59419 AN: 85128

European-Finnish (FIN) AF: 0.517 AC: 26984 AN: 52180

Middle Eastern (MID) AF: 0.660 AC: 3499 AN: 5302

European-Non Finnish (NFE) AF: 0.598 AC: 659933 AN: 1103246

Other (OTH) AF: 0.614 AC: 36742 AN: 59852

GnomAD4 genome AF: 0.604 AC: 91867 AN: 152164 Hom.: 27935 Cov.: 34 AF XY: 0.600 AC XY: 44621 AN XY: 74388

African (AFR) AF: 0.631 AC: 26195 AN: 41532

American (AMR) AF: 0.533 AC: 8161 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.610 AC: 2117 AN: 3470

East Asian (EAS) AF: 0.781 AC: 4033 AN: 5162

South Asian (SAS) AF: 0.679 AC: 3276 AN: 4828

European-Finnish (FIN) AF: 0.505 AC: 5339 AN: 10578

Middle Eastern (MID) AF: 0.684 AC: 201 AN: 294

European-Non Finnish (NFE) AF: 0.598 AC: 40675 AN: 67974

Other (OTH) AF: 0.602 AC: 1274 AN: 2116

Alfa AF: 0.599 Hom.: 67365

Bravo AF: 0.603

Asia WGS AF: 0.673 AC: 2339 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Tyrosinemia type I Benign:1

Jun 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.15
DANN	Benign	0.51
PhyloP100		-0.57
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: rs1370273; hg19: chr15-80452268;