4-73436498-T-A

Variant names:

• chr4-73436498-T-A
• rs3796676
• NM_001134.3:c.85+151T>A

Variant summary

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

The NM_001134.3(AFP):​c.85+151T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.455 in 550,668 control chromosomes in the GnomAD database, including 58,564 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 (16605 hom., cov: 32)
  • Exomes 𝑓: 0.45 (41959 hom.)
• Consequence: AFP NM_001134.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.176
• Publications: 5 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=-0.81).
• 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.85+151T>A		intron	N/A	NP_001125.1
	AFP	NM_001354717.2		c.-248+151T>A		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.85+151T>A		intron	N/A	ENSP00000379138.2
	AFP	ENST00000513720.5	TSL:1	n.147-662T>A		intron	N/A
	AFP	ENST00000515675.1	TSL:1	n.267-662T>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.464 AC: 70197 AN: 151424 Hom.: 16574 Cov.: 32

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: 0.469

Gnomad MID AF: 0.481

Gnomad NFE AF: 0.425

Gnomad OTH AF: 0.489

GnomAD4 exome AF: 0.452 AC: 180465 AN: 399126 Hom.: 41959 AF XY: 0.451 AC XY: 96007 AN XY: 212776

African (AFR) AF: 0.495 AC: 5391 AN: 10894

American (AMR) AF: 0.553 AC: 7457 AN: 13484

Ashkenazi Jewish (ASJ) AF: 0.557 AC: 6603 AN: 11854

East Asian (EAS) AF: 0.460 AC: 12448 AN: 27036

South Asian (SAS) AF: 0.462 AC: 16394 AN: 35476

European-Finnish (FIN) AF: 0.470 AC: 14259 AN: 30348

Middle Eastern (MID) AF: 0.505 AC: 854 AN: 1692

European-Non Finnish (NFE) AF: 0.433 AC: 106408 AN: 245664

Other (OTH) AF: 0.470 AC: 10651 AN: 22678

GnomAD4 genome AF: 0.464 AC: 70290 AN: 151542 Hom.: 16605 Cov.: 32 AF XY: 0.468 AC XY: 34655 AN XY: 74060

African (AFR) AF: 0.490 AC: 20295 AN: 41414

American (AMR) AF: 0.547 AC: 8315 AN: 15198

Ashkenazi Jewish (ASJ) AF: 0.558 AC: 1932 AN: 3462

East Asian (EAS) AF: 0.432 AC: 2235 AN: 5170

South Asian (SAS) AF: 0.476 AC: 2296 AN: 4824

European-Finnish (FIN) AF: 0.469 AC: 4909 AN: 10468

Middle Eastern (MID) AF: 0.483 AC: 142 AN: 294

European-Non Finnish (NFE) AF: 0.425 AC: 28746 AN: 67700

Other (OTH) AF: 0.492 AC: 1035 AN: 2102

Alfa AF: 0.440 Hom.: 1817

Bravo AF: 0.470

Asia WGS AF: 0.506 AC: 1729 AN: 3412

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	9.8
DANN	Benign	0.68
PhyloP100		0.18
PromoterAI		-0.0088	Neutral
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: rs3796676; hg19: chr4-74302215;