chr15-80158143-C-T

Variant names:

• chr15-80158143-C-T
• rs28733633
• NM_000137.4:c.165C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_000137.4(FAH):​c.165C>T​(p.Leu55Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00148 in 1,613,854 control chromosomes in the GnomAD database, including 31 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. L55L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0076 (18 hom., cov: 32)
  • Exomes 𝑓: 0.00084 (13 hom.)
• Consequence: FAH NM_000137.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.0270
• Publications: 2 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.36).
• BP6: Variant 15-80158143-C-T is Benign according to our data. Variant chr15-80158143-C-T is described in ClinVar as Benign. ClinVar VariationId is 380509.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.027 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00762 (1160/152326) while in subpopulation AFR AF = 0.0261 (1086/41570). AF 95% confidence interval is 0.0248. There are 18 homozygotes in GnomAd4. There are 532 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 18 AR gene

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.165C>T	p.Leu55Leu	synonymous	Exon 2 of 14	NP_000128.1	A0A384P5L6
	FAH	NM_001374377.1		c.165C>T	p.Leu55Leu	synonymous	Exon 3 of 15	NP_001361306.1	A0A384P5L6
	FAH	NM_001374380.1		c.165C>T	p.Leu55Leu	synonymous	Exon 3 of 15	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.165C>T	p.Leu55Leu	synonymous	Exon 2 of 14	ENSP00000453347.2	P16930-1
	FAH	ENST00000539156.5	TSL:1	n.2193C>T		non_coding_transcript_exon	Exon 1 of 13
	FAH	ENST00000874657.1		c.267C>T	p.Leu89Leu	synonymous	Exon 4 of 16	ENSP00000544716.1

Frequencies

GnomAD3 genomes AF: 0.00761 AC: 1158 AN: 152208 Hom.: 18 Cov.: 32

Gnomad AFR AF: 0.0262

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00281

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.00669

GnomAD2 exomes AF: 0.00208 AC: 523 AN: 251496 AF XY: 0.00159

Gnomad AFR exome AF: 0.0255

Gnomad AMR exome AF: 0.00188

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000334

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000844 AC: 1233 AN: 1461528 Hom.: 13 Cov.: 32 AF XY: 0.000732 AC XY: 532 AN XY: 727110

African (AFR) AF: 0.0252 AC: 844 AN: 33462

American (AMR) AF: 0.00190 AC: 85 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000153 AC: 4 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000696 AC: 6 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00312 AC: 18 AN: 5768

European-Non Finnish (NFE) AF: 0.000139 AC: 155 AN: 1111688

Other (OTH) AF: 0.00200 AC: 121 AN: 60382

GnomAD4 genome AF: 0.00762 AC: 1160 AN: 152326 Hom.: 18 Cov.: 32 AF XY: 0.00714 AC XY: 532 AN XY: 74482

African (AFR) AF: 0.0261 AC: 1086 AN: 41570

American (AMR) AF: 0.00281 AC: 43 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000176 AC: 12 AN: 68036

Other (OTH) AF: 0.00662 AC: 14 AN: 2116

Alfa AF: 0.00285 Hom.: 8

Bravo AF: 0.00825

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000178

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.36
CADD	Benign	7.3
DANN	Benign	0.79
PhyloP100		-0.027
Mutation Taster		=295/5	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
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

Other links and lift over

dbSNP: rs28733633; hg19: chr15-80450485;