rs112474268

Variant names:

• chr15-80152950-G-C
• rs112474268
• ENST00000960162.1:c.-105G>C

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.-30+45G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.271 in 975,720 control chromosomes in the GnomAD database, including 37,728 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.23 (4547 hom., cov: 28)
  • Exomes 𝑓: 0.28 (33181 hom.)
• Consequence: FAH NM_001374377.1 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -2.77
• 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: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), Orphanet, G2P, Ambry Genetics, Myriad Women’s Health, 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 15-80152950-G-C is Benign according to our data. Variant chr15-80152950-G-C is described in ClinVar as Benign. ClinVar VariationId is 317196.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.296 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.-30+45G>C		intron	N/A	NP_001361306.1	A0A384P5L6
	FAH	NM_001374380.1		c.-29-76G>C		intron	N/A	NP_001361309.1	A0A384P5L6
	FAH	NM_000137.4	MANE Select	c.-105G>C		upstream_gene	N/A	NP_000128.1	A0A384P5L6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FAH	ENST00000960162.1		c.-105G>C		5_prime_UTR	Exon 1 of 14	ENSP00000630221.1
	FAH	ENST00000558767.6	TSL:2	c.-105G>C		5_prime_UTR	Exon 1 of 5	ENSP00000507680.1	A0A804HJX2
	FAH	ENST00000874657.1		c.-30+45G>C		intron	N/A	ENSP00000544716.1

Frequencies

GnomAD3 genomes AF: 0.232 AC: 34686 AN: 149758 Hom.: 4553 Cov.: 28

Gnomad AFR AF: 0.114

Gnomad AMI AF: 0.458

Gnomad AMR AF: 0.226

Gnomad ASJ AF: 0.248

Gnomad EAS AF: 0.136

Gnomad SAS AF: 0.222

Gnomad FIN AF: 0.287

Gnomad MID AF: 0.172

Gnomad NFE AF: 0.300

Gnomad OTH AF: 0.235

GnomAD4 exome AF: 0.279 AC: 230060 AN: 825848 Hom.: 33181 Cov.: 11 AF XY: 0.278 AC XY: 119872 AN XY: 431872

African (AFR) AF: 0.117 AC: 2472 AN: 21184

American (AMR) AF: 0.215 AC: 8396 AN: 38974

Ashkenazi Jewish (ASJ) AF: 0.258 AC: 5503 AN: 21302

East Asian (EAS) AF: 0.157 AC: 5483 AN: 34886

South Asian (SAS) AF: 0.232 AC: 16453 AN: 71066

European-Finnish (FIN) AF: 0.285 AC: 10157 AN: 35698

Middle Eastern (MID) AF: 0.266 AC: 1052 AN: 3956

European-Non Finnish (NFE) AF: 0.304 AC: 170146 AN: 559318

Other (OTH) AF: 0.263 AC: 10398 AN: 39464

GnomAD4 genome AF: 0.232 AC: 34698 AN: 149872 Hom.: 4547 Cov.: 28 AF XY: 0.230 AC XY: 16846 AN XY: 73120

African (AFR) AF: 0.114 AC: 4641 AN: 40844

American (AMR) AF: 0.226 AC: 3417 AN: 15118

Ashkenazi Jewish (ASJ) AF: 0.248 AC: 855 AN: 3444

East Asian (EAS) AF: 0.136 AC: 678 AN: 4972

South Asian (SAS) AF: 0.223 AC: 1052 AN: 4718

European-Finnish (FIN) AF: 0.287 AC: 2945 AN: 10252

Middle Eastern (MID) AF: 0.153 AC: 44 AN: 288

European-Non Finnish (NFE) AF: 0.300 AC: 20170 AN: 67260

Other (OTH) AF: 0.234 AC: 486 AN: 2080

Alfa AF: 0.271 Hom.: 700

Bravo AF: 0.220

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Tyrosinemia type I (3)
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	3.3
DANN	Benign	0.53
PhyloP100		-2.8
PromoterAI		-0.015	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs112474268; hg19: chr15-80445292;