NM_001374377.1:c.-58G>A

Variant names:

• chr15-80152877-G-A
• rs56043846
• NM_001374377.1:c.-58G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001374377.1(FAH):​c.-58G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.23 (4292 hom., cov: 19)
  • Exomes 𝑓: 0.27 (17354 hom.)
• Consequence: FAH NM_001374377.1 5_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.908
• Publications: 7 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: Ambry Genetics, Myriad Women’s Health, G2P, Labcorp Genetics (formerly Invitae), Orphanet, ClinGen, Laboratory for Molecular Medicine

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 15-80152877-G-A is Benign according to our data. Variant chr15-80152877-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 369102.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.292 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001374377.1. 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_001374377.1		c.-58G>A		5_prime_UTR	Exon 1 of 15	NP_001361306.1	A0A384P5L6
	FAH	NM_001374380.1		c.-30+36G>A		intron	N/A	NP_001361309.1	A0A384P5L6
	FAH	NM_000137.4	MANE Select	c.-178G>A		upstream_gene	N/A	NP_000128.1	A0A384P5L6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FAH	ENST00000407106.5	TSL:5	c.-58G>A		5_prime_UTR	Exon 1 of 15	ENSP00000385080.1	P16930-1
	FAH	ENST00000874652.1		c.-83G>A		5_prime_UTR	Exon 1 of 15	ENSP00000544711.1
	FAH	ENST00000874654.1		c.-41G>A		5_prime_UTR	Exon 1 of 15	ENSP00000544713.1

Frequencies

GnomAD3 genomes AF: 0.225 AC: 32102 AN: 142456 Hom.: 4297 Cov.: 19

Gnomad AFR AF: 0.105

Gnomad AMI AF: 0.447

Gnomad AMR AF: 0.218

Gnomad ASJ AF: 0.248

Gnomad EAS AF: 0.136

Gnomad SAS AF: 0.207

Gnomad FIN AF: 0.268

Gnomad MID AF: 0.171

Gnomad NFE AF: 0.296

Gnomad OTH AF: 0.228

GnomAD4 exome AF: 0.269 AC: 123429 AN: 459126 Hom.: 17354 Cov.: 4 AF XY: 0.267 AC XY: 64912 AN XY: 242774

African (AFR) AF: 0.116 AC: 1545 AN: 13370

American (AMR) AF: 0.218 AC: 5299 AN: 24292

Ashkenazi Jewish (ASJ) AF: 0.259 AC: 3683 AN: 14206

East Asian (EAS) AF: 0.157 AC: 4779 AN: 30392

South Asian (SAS) AF: 0.229 AC: 11372 AN: 49676

European-Finnish (FIN) AF: 0.286 AC: 8353 AN: 29250

Middle Eastern (MID) AF: 0.269 AC: 536 AN: 1990

European-Non Finnish (NFE) AF: 0.300 AC: 81009 AN: 269754

Other (OTH) AF: 0.262 AC: 6853 AN: 26196

GnomAD4 genome AF: 0.225 AC: 32114 AN: 142558 Hom.: 4292 Cov.: 19 AF XY: 0.223 AC XY: 15412 AN XY: 69066

African (AFR) AF: 0.105 AC: 4060 AN: 38504

American (AMR) AF: 0.218 AC: 3149 AN: 14426

Ashkenazi Jewish (ASJ) AF: 0.248 AC: 831 AN: 3348

East Asian (EAS) AF: 0.136 AC: 644 AN: 4744

South Asian (SAS) AF: 0.208 AC: 898 AN: 4310

European-Finnish (FIN) AF: 0.268 AC: 2507 AN: 9346

Middle Eastern (MID) AF: 0.154 AC: 43 AN: 280

European-Non Finnish (NFE) AF: 0.296 AC: 19169 AN: 64814

Other (OTH) AF: 0.226 AC: 443 AN: 1958

Alfa AF: 0.260 Hom.: 1635

Bravo AF: 0.221

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Hypertyrosinemia (1)
-	-	1	Tyrosinemia type I (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	7.2
DANN	Benign	0.56
PhyloP100		-0.91
PromoterAI		0.13	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.1
Mutation Taster		=300/0	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: rs56043846; hg19: chr15-80445219; COSMIC: COSV55722092; COSMIC: COSV55722092;