15-80177544-A-G

Variant names:

• chr15-80177544-A-G
• rs76338717
• NM_000137.4:c.921A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_000137.4(FAH):​c.921A>G​(p.Gly307Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00159 in 1,613,976 control chromosomes in the GnomAD database, including 73 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. G307G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0020 (7 hom., cov: 32)
  • Exomes 𝑓: 0.0016 (66 hom.)
• Consequence: FAH NM_000137.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.333
• 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BP6: Variant 15-80177544-A-G is Benign according to our data. Variant chr15-80177544-A-G is described in ClinVar as Benign. ClinVar VariationId is 281004.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.333 with no splicing effect.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00197 (300/152360) while in subpopulation EAS AF = 0.0534 (277/5190). AF 95% confidence interval is 0.0482. There are 7 homozygotes in GnomAd4. There are 162 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 7 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.921A>G	p.Gly307Gly	synonymous	Exon 11 of 14	NP_000128.1	A0A384P5L6
	FAH	NM_001374377.1		c.921A>G	p.Gly307Gly	synonymous	Exon 12 of 15	NP_001361306.1	A0A384P5L6
	FAH	NM_001374380.1		c.921A>G	p.Gly307Gly	synonymous	Exon 12 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.921A>G	p.Gly307Gly	synonymous	Exon 11 of 14	ENSP00000453347.2	P16930-1
	FAH	ENST00000539156.5	TSL:1	n.2949A>G		non_coding_transcript_exon	Exon 10 of 13
	FAH	ENST00000874657.1		c.1023A>G	p.Gly341Gly	synonymous	Exon 13 of 16	ENSP00000544716.1

Frequencies

GnomAD3 genomes AF: 0.00197 AC: 300 AN: 152242 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0534

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00411 AC: 1033 AN: 251478 AF XY: 0.00372

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0551

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000977

GnomAD4 exome AF: 0.00155 AC: 2267 AN: 1461616 Hom.: 66 Cov.: 29 AF XY: 0.00145 AC XY: 1058 AN XY: 727154

African (AFR) AF: 0.000179 AC: 6 AN: 33470

American (AMR) AF: 0.000134 AC: 6 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0507 AC: 2012 AN: 39690

South Asian (SAS) AF: 0.000313 AC: 27 AN: 86256

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

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5766

European-Non Finnish (NFE) AF: 0.0000117 AC: 13 AN: 1111764

Other (OTH) AF: 0.00331 AC: 200 AN: 60392

GnomAD4 genome AF: 0.00197 AC: 300 AN: 152360 Hom.: 7 Cov.: 32 AF XY: 0.00217 AC XY: 162 AN XY: 74508

African (AFR) AF: 0.0000722 AC: 3 AN: 41580

American (AMR) AF: 0.000457 AC: 7 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.0534 AC: 277 AN: 5190

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68038

Other (OTH) AF: 0.00331 AC: 7 AN: 2116

Alfa AF: 0.00200 Hom.: 3

Bravo AF: 0.00228

Asia WGS AF: 0.0210 AC: 73 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	9.5
DANN	Benign	0.76
PhyloP100		0.33
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.20		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.20		Position offset: -4

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

Other links and lift over

dbSNP: rs76338717; hg19: chr15-80469886;