4-73442355-G-A

Variant names:

• chr4-73442355-G-A
• NM_001134.3:c.542G>A
• AFP p.Trp181*

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_001134.3(AFP):​c.542G>A​(p.Trp181*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: AFP NM_001134.3 stop_gained
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0510
• Publications: 0 publications found

Genes affected

AFP (HGNC:317): (alpha fetoprotein) This gene encodes alpha-fetoprotein, a major plasma protein produced by the yolk sac and the liver during fetal life. Alpha-fetoprotein expression in adults is often associated with hepatocarcinoma and with teratoma, and has prognostic value for managing advanced gastric cancer. However, hereditary persistance of alpha-fetoprotein may also be found in individuals with no obvious pathology. The protein is thought to be the fetal counterpart of serum albumin, and the alpha-fetoprotein and albumin genes are present in tandem in the same transcriptional orientation on chromosome 4. Alpha-fetoprotein is found in monomeric as well as dimeric and trimeric forms, and binds copper, nickel, fatty acids and bilirubin. The level of alpha-fetoprotein in amniotic fluid is used to measure renal loss of protein to screen for spina bifida and anencephaly. [provided by RefSeq, Oct 2019]

AFP Gene-Disease associations (from GenCC):

• hereditary persistence of alpha-fetoprotein

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• congenital deficiency in alpha-fetoprotein

  Inheritance: AR Classification: NO_KNOWN Submitted by: Ambry Genetics

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001134.3. 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
	AFP	NM_001134.3	MANE Select	c.542G>A	p.Trp181*	stop_gained	Exon 5 of 15	NP_001125.1	P02771
	AFP	NM_001354717.2		c.68G>A	p.Trp23*	stop_gained	Exon 6 of 16	NP_001341646.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AFP	ENST00000395792.7	TSL:1 MANE Select	c.542G>A	p.Trp181*	stop_gained	Exon 5 of 15	ENSP00000379138.2	P02771
	AFP	ENST00000226359.2	TSL:5	c.542G>A	p.Trp181*	stop_gained	Exon 5 of 14	ENSP00000226359.2	J3KMX3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Uncertain	0.060
CADD	Pathogenic	34
DANN	Benign	0.96
Eigen	Benign	-0.022
Eigen_PC	Benign	-0.36
FATHMM_MKL	Benign	0.12	N
PhyloP100		0.051
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=49/151	disease causing (fs/PTC)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.25		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.25		Position offset: 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

hg19: chr4-74308072;