rs60585303

Variant names:

• chr15-80181163-A-G
• rs60585303
• NM_000137.4:c.1180+4A>G

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_000137.4(FAH):​c.1180+4A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00834 in 1,597,466 control chromosomes in the GnomAD database, including 921 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.042 (455 hom., cov: 32)
  • Exomes 𝑓: 0.0048 (466 hom.)
• Consequence: FAH NM_000137.4 splice_region, intron
• Scores: Splicing: ADA: 0.8486
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.731
• Publications: 1 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: G2P, Myriad Women's Health, ClinGen, Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics, Laboratory for Molecular Medicine

ACMG classification

Our verdict: Benign. The variant received -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.37).
• BP6: Variant 15-80181163-A-G is Benign according to our data. Variant chr15-80181163-A-G is described in ClinVar as Benign. ClinVar VariationId is 255278.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.144 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.1180+4A>G		splice_region intron	N/A	NP_000128.1	A0A384P5L6
	FAH	NM_001374377.1		c.1180+4A>G		splice_region intron	N/A	NP_001361306.1	A0A384P5L6
	FAH	NM_001374380.1		c.1180+4A>G		splice_region intron	N/A	NP_001361309.1	A0A384P5L6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FAH	ENST00000561421.6	TSL:1 MANE Select	c.1180+4A>G		splice_region intron	N/A	ENSP00000453347.2	P16930-1
	FAH	ENST00000539156.5	TSL:1	n.3208+4A>G		splice_region intron	N/A
	FAH	ENST00000874657.1		c.1282+4A>G		splice_region intron	N/A	ENSP00000544716.1

Frequencies

GnomAD3 genomes AF: 0.0423 AC: 6436 AN: 152138 Hom.: 453 Cov.: 32

Gnomad AFR AF: 0.147

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0144

Gnomad ASJ AF: 0.00432

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.000632

Gnomad OTH AF: 0.0282

GnomAD2 exomes AF: 0.0118 AC: 2975 AN: 251354 AF XY: 0.00856

Gnomad AFR exome AF: 0.154

Gnomad AMR exome AF: 0.00908

Gnomad ASJ exome AF: 0.00278

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000695

Gnomad OTH exome AF: 0.00798

GnomAD4 exome AF: 0.00475 AC: 6871 AN: 1445210 Hom.: 466 Cov.: 26 AF XY: 0.00411 AC XY: 2956 AN XY: 719940

African (AFR) AF: 0.157 AC: 5220 AN: 33150

American (AMR) AF: 0.0101 AC: 449 AN: 44650

Ashkenazi Jewish (ASJ) AF: 0.00308 AC: 80 AN: 26008

East Asian (EAS) AF: 0.00 AC: 0 AN: 39538

South Asian (SAS) AF: 0.000268 AC: 23 AN: 85852

European-Finnish (FIN) AF: 0.0000188 AC: 1 AN: 53256

Middle Eastern (MID) AF: 0.00995 AC: 57 AN: 5728

European-Non Finnish (NFE) AF: 0.000459 AC: 504 AN: 1097284

Other (OTH) AF: 0.00899 AC: 537 AN: 59744

GnomAD4 genome AF: 0.0424 AC: 6451 AN: 152256 Hom.: 455 Cov.: 32 AF XY: 0.0407 AC XY: 3030 AN XY: 74444

African (AFR) AF: 0.147 AC: 6105 AN: 41526

American (AMR) AF: 0.0144 AC: 220 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00432 AC: 15 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5164

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4826

European-Finnish (FIN) AF: 0.0000941 AC: 1 AN: 10622

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.000632 AC: 43 AN: 68028

Other (OTH) AF: 0.0279 AC: 59 AN: 2114

Alfa AF: 0.0215 Hom.: 117

Bravo AF: 0.0483

Asia WGS AF: 0.00953 AC: 33 AN: 3478

EpiCase AF: 0.00104

EpiControl AF: 0.000771

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	Tyrosinemia type I (2)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.37
CADD	Benign	17
DANN	Benign	0.91
PhyloP100		0.73
Mutation Taster		=93/7	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.85
dbscSNV1_RF	Benign	0.56
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs60585303;

hg19: chr15-80473505;