chr4-73447498-ACT-A

Variant names:

• chr4-73447498-ACT-A
• rs387906580
• NM_001134.3:c.883_884delCT

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_001134.3(AFP):​c.883_884delCT​(p.Leu295ValfsTer25) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,742 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: AFP NM_001134.3 frameshift
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: -0.111
• Publications: 2 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 11 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
• PP5: Variant 4-73447498-ACT-A is Pathogenic according to our data. Variant chr4-73447498-ACT-A is described in ClinVar as Pathogenic. ClinVar VariationId is 18169.Status of the report is no_assertion_criteria_provided, 0 stars.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AFP	NM_001134.3	MANE Select	c.883_884delCT	p.Leu295ValfsTer25	frameshift	Exon 8 of 15	NP_001125.1
	AFP	NM_001354717.2		c.409_410delCT	p.Leu137ValfsTer25	frameshift	Exon 9 of 16	NP_001341646.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AFP	ENST00000395792.7	TSL:1 MANE Select	c.883_884delCT	p.Leu295ValfsTer25	frameshift	Exon 8 of 15	ENSP00000379138.2
	AFP	ENST00000226359.2	TSL:5	c.883_884delCT	p.Leu295ValfsTer25	frameshift	Exon 8 of 14	ENSP00000226359.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459742 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 726224

African (AFR) AF: 0.00 AC: 0 AN: 33372

American (AMR) AF: 0.00 AC: 0 AN: 44510

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26074

East Asian (EAS) AF: 0.00 AC: 0 AN: 39666

South Asian (SAS) AF: 0.00 AC: 0 AN: 85950

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53380

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5280

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111212

Other (OTH) AF: 0.00 AC: 0 AN: 60298

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Alpha-fetoprotein deficiency Pathogenic:1

Mar 01, 2009

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.11
Mutation Taster		=22/178	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs387906580; hg19: chr4-74313215;