4-73436824-T-C

Variant names:

• chr4-73436824-T-C
• rs28532518
• NM_001134.3:c.86-336T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001134.3(AFP):​c.86-336T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.464 in 151,584 control chromosomes in the GnomAD database, including 16,606 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.46 (16606 hom., cov: 31)
• Consequence: AFP NM_001134.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.181
• Publications: 3 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.537 is higher than 0.05.

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.86-336T>C		intron	N/A	NP_001125.1
	AFP	NM_001354717.2		c.-247-336T>C		intron	N/A	NP_001341646.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AFP	ENST00000395792.7	TSL:1 MANE Select	c.86-336T>C		intron	N/A	ENSP00000379138.2
	AFP	ENST00000513720.5	TSL:1	n.147-336T>C		intron	N/A
	AFP	ENST00000515675.1	TSL:1	n.267-336T>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.464 AC: 70225 AN: 151466 Hom.: 16575 Cov.: 31

Gnomad AFR AF: 0.489

Gnomad AMI AF: 0.423

Gnomad AMR AF: 0.547

Gnomad ASJ AF: 0.558

Gnomad EAS AF: 0.433

Gnomad SAS AF: 0.476

Gnomad FIN AF: 0.471

Gnomad MID AF: 0.484

Gnomad NFE AF: 0.424

Gnomad OTH AF: 0.490

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.464 AC: 70317 AN: 151584 Hom.: 16606 Cov.: 31 AF XY: 0.468 AC XY: 34698 AN XY: 74096

African (AFR) AF: 0.490 AC: 20291 AN: 41412

American (AMR) AF: 0.547 AC: 8324 AN: 15220

Ashkenazi Jewish (ASJ) AF: 0.558 AC: 1931 AN: 3462

East Asian (EAS) AF: 0.433 AC: 2230 AN: 5154

South Asian (SAS) AF: 0.476 AC: 2287 AN: 4808

European-Finnish (FIN) AF: 0.471 AC: 4962 AN: 10544

Middle Eastern (MID) AF: 0.486 AC: 142 AN: 292

European-Non Finnish (NFE) AF: 0.424 AC: 28725 AN: 67674

Other (OTH) AF: 0.493 AC: 1039 AN: 2106

Alfa AF: 0.275 Hom.: 592

Bravo AF: 0.470

Asia WGS AF: 0.507 AC: 1761 AN: 3470

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	3.0
DANN	Benign	0.49
PhyloP100		-0.18
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs28532518; hg19: chr4-74302541;