rs2278204

Variant names:

• chr15-80162365-G-A
• rs2278204
• NM_000137.4:c.455+29G>A

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.455+29G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0188 in 1,563,212 control chromosomes in the GnomAD database, including 2,490 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.024 (293 hom., cov: 33)
  • Exomes 𝑓: 0.018 (2197 hom.)
• Consequence: FAH NM_000137.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.202
• Publications: 4 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=-0.81).
• BP6: Variant 15-80162365-G-A is Benign according to our data. Variant chr15-80162365-G-A is described in ClinVar as Benign. ClinVar VariationId is 255281.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.244 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FAH	NM_000137.4	c.455+29G>A		intron_variant	Intron 5 of 13	ENST00000561421.6	NP_000128.1
FAH	NM_001374377.1	c.455+29G>A		intron_variant	Intron 6 of 14		NP_001361306.1
FAH	NM_001374380.1	c.455+29G>A		intron_variant	Intron 6 of 14		NP_001361309.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FAH	ENST00000561421.6	c.455+29G>A		intron_variant	Intron 5 of 13	1	NM_000137.4	ENSP00000453347.2

Frequencies

GnomAD3 genomes AF: 0.0243 AC: 3694 AN: 152198 Hom.: 293 Cov.: 33

Gnomad AFR AF: 0.00511

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0937

Gnomad ASJ AF: 0.0144

Gnomad EAS AF: 0.256

Gnomad SAS AF: 0.0919

Gnomad FIN AF: 0.00264

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00226

Gnomad OTH AF: 0.0239

GnomAD2 exomes AF: 0.0533 AC: 13412 AN: 251420 AF XY: 0.0496

Gnomad AFR exome AF: 0.00480

Gnomad AMR exome AF: 0.156

Gnomad ASJ exome AF: 0.0139

Gnomad EAS exome AF: 0.265

Gnomad FIN exome AF: 0.00217

Gnomad NFE exome AF: 0.00147

Gnomad OTH exome AF: 0.0285

GnomAD4 exome AF: 0.0182 AC: 25651 AN: 1410896 Hom.: 2197 Cov.: 23 AF XY: 0.0191 AC XY: 13495 AN XY: 705038

African (AFR) AF: 0.00275 AC: 89 AN: 32342

American (AMR) AF: 0.149 AC: 6633 AN: 44646

Ashkenazi Jewish (ASJ) AF: 0.0119 AC: 306 AN: 25804

East Asian (EAS) AF: 0.230 AC: 9084 AN: 39434

South Asian (SAS) AF: 0.0774 AC: 6598 AN: 85280

European-Finnish (FIN) AF: 0.00213 AC: 114 AN: 53400

Middle Eastern (MID) AF: 0.00600 AC: 34 AN: 5664

European-Non Finnish (NFE) AF: 0.00104 AC: 1103 AN: 1065574

Other (OTH) AF: 0.0288 AC: 1690 AN: 58752

GnomAD4 genome AF: 0.0243 AC: 3700 AN: 152316 Hom.: 293 Cov.: 33 AF XY: 0.0275 AC XY: 2046 AN XY: 74472

African (AFR) AF: 0.00510 AC: 212 AN: 41582

American (AMR) AF: 0.0941 AC: 1440 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0144 AC: 50 AN: 3470

East Asian (EAS) AF: 0.256 AC: 1322 AN: 5170

South Asian (SAS) AF: 0.0916 AC: 442 AN: 4826

European-Finnish (FIN) AF: 0.00264 AC: 28 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00226 AC: 154 AN: 68026

Other (OTH) AF: 0.0246 AC: 52 AN: 2112

Alfa AF: 0.0185 Hom.: 32

Bravo AF: 0.0302

Asia WGS AF: 0.158 AC: 550 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

Jul 01, 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	-0.81
CADD	Benign	11
DANN	Benign	0.57
PhyloP100		0.20
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs2278204; hg19: chr15-80454707; COSMIC: COSV55722465; COSMIC: COSV55722465;