chr4-73445127-A-G

Variant names:

• chr4-73445127-A-G
• rs2298839
• NM_001134.3:c.843+5A>G

Variant summary

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

The NM_001134.3(AFP):​c.843+5A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.558 in 1,612,764 control chromosomes in the GnomAD database, including 253,780 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/2 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.52 (20978 hom., cov: 31)
  • Exomes 𝑓: 0.56 (232802 hom.)
• Consequence: AFP NM_001134.3 splice_region, intron
• Scores: Splicing: ADA: 0.0005286
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.109
• Publications: 19 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 (EAS) allele frequency at 95% confidence interval = 0.649 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AFP	NM_001134.3	MANE Select	c.843+5A>G		splice_region intron	N/A	NP_001125.1
	AFP	NM_001354717.2		c.369+5A>G		splice_region intron	N/A	NP_001341646.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AFP	ENST00000395792.7	TSL:1 MANE Select	c.843+5A>G		splice_region intron	N/A	ENSP00000379138.2
	AFP	ENST00000226359.2	TSL:5	c.843+5A>G		splice_region intron	N/A	ENSP00000226359.2

Frequencies

GnomAD3 genomes AF: 0.520 AC: 78965 AN: 151818 Hom.: 20984 Cov.: 31

Gnomad AFR AF: 0.439

Gnomad AMI AF: 0.578

Gnomad AMR AF: 0.457

Gnomad ASJ AF: 0.436

Gnomad EAS AF: 0.667

Gnomad SAS AF: 0.497

Gnomad FIN AF: 0.541

Gnomad MID AF: 0.525

Gnomad NFE AF: 0.576

Gnomad OTH AF: 0.483

GnomAD2 exomes AF: 0.541 AC: 135915 AN: 251370 AF XY: 0.544

Gnomad AFR exome AF: 0.441

Gnomad AMR exome AF: 0.462

Gnomad ASJ exome AF: 0.448

Gnomad EAS exome AF: 0.686

Gnomad FIN exome AF: 0.543

Gnomad NFE exome AF: 0.576

Gnomad OTH exome AF: 0.534

GnomAD4 exome AF: 0.562 AC: 821274 AN: 1460826 Hom.: 232802 Cov.: 43 AF XY: 0.562 AC XY: 408108 AN XY: 726726

African (AFR) AF: 0.433 AC: 14491 AN: 33452

American (AMR) AF: 0.460 AC: 20573 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.447 AC: 11669 AN: 26102

East Asian (EAS) AF: 0.667 AC: 26445 AN: 39658

South Asian (SAS) AF: 0.501 AC: 43243 AN: 86232

European-Finnish (FIN) AF: 0.548 AC: 29242 AN: 53380

Middle Eastern (MID) AF: 0.484 AC: 2786 AN: 5758

European-Non Finnish (NFE) AF: 0.576 AC: 640266 AN: 1111194

Other (OTH) AF: 0.540 AC: 32559 AN: 60348

GnomAD4 genome AF: 0.520 AC: 78973 AN: 151938 Hom.: 20978 Cov.: 31 AF XY: 0.517 AC XY: 38397 AN XY: 74260

African (AFR) AF: 0.438 AC: 18163 AN: 41444

American (AMR) AF: 0.457 AC: 6969 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.436 AC: 1512 AN: 3468

East Asian (EAS) AF: 0.667 AC: 3449 AN: 5168

South Asian (SAS) AF: 0.496 AC: 2386 AN: 4806

European-Finnish (FIN) AF: 0.541 AC: 5699 AN: 10540

Middle Eastern (MID) AF: 0.524 AC: 154 AN: 294

European-Non Finnish (NFE) AF: 0.576 AC: 39108 AN: 67936

Other (OTH) AF: 0.477 AC: 1007 AN: 2110

Alfa AF: 0.555 Hom.: 99169

Bravo AF: 0.514

Asia WGS AF: 0.530 AC: 1844 AN: 3478

EpiCase AF: 0.559

EpiControl AF: 0.557

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	13
DANN	Benign	0.82
PhyloP100		0.11
Mutation Taster		=97/3	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00053
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: rs2298839; hg19: chr4-74310844; COSMIC: COSV56924958;