rs1449927772

Positions:

• chr15-80186144-G-A
• chr15-80186144-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_000137.4(FAH):​c.1195G>A​(p.Asp399Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,810 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: FAH NM_000137.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.737

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.30752927).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FAH	NM_000137.4	c.1195G>A	p.Asp399Asn	missense_variant	14/14	ENST00000561421.6	NP_000128.1
FAH	NM_001374377.1	c.1195G>A	p.Asp399Asn	missense_variant	15/15		NP_001361306.1
FAH	NM_001374380.1	c.1195G>A	p.Asp399Asn	missense_variant	15/15		NP_001361309.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FAH	ENST00000561421.6	c.1195G>A	p.Asp399Asn	missense_variant	14/14	1	NM_000137.4	ENSP00000453347	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461810 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727218

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Aug 03, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.044	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	8.1
DANN	Benign	0.94
DEOGEN2	Uncertain	0.70	D;D;D
Eigen	Benign	-0.71
Eigen_PC	Benign	-0.67
FATHMM_MKL	Benign	0.13	N
LIST_S2	Uncertain	0.94	.;.;D
M_CAP	Pathogenic	0.32	D
MetaRNN	Benign	0.31	T;T;T
MetaSVM	Uncertain	0.050	D
MutationAssessor	Benign	0.93	L;L;L
MutationTaster	Benign	0.96	D;D;D;D
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-1.4	N;N;N
REVEL	Benign	0.21
Sift	Benign	0.33	T;T;T
Sift4G	Benign	0.17	T;T;T
Polyphen		0.0	B;B;B
Vest4		0.058
MutPred		0.44		Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);
MVP		0.87
MPC		0.22
ClinPred		0.11	T
GERP RS		1.5
Varity_R		0.062
gMVP		0.50

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

Publications

LitVar

Other links and lift over

dbSNP: rs1449927772; hg19: chr15-80478486; COSMIC: COSV105066283;