rs2298839

Positions:

• chr4-73445127-A-G
• chr4-73445127-A-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_001134.3(AFP):​c.843+5A>G variant causes a splice donor 5th base, 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. Variant has been reported in Lovd as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.52 (20978 hom., cov: 31)
  • Exomes 𝑓: 0.56 (232802 hom.)
• Consequence: AFP NM_001134.3 splice_donor_5th_base, intron
• Scores: Splicing: ADA: 0.0005286
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.109

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]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 4-73445127-A-G is Benign according to our data. Variant chr4-73445127-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.649 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AFP	NM_001134.3	c.843+5A>G		splice_donor_5th_base_variant, intron_variant		ENST00000395792.7
AFP	NM_001354717.2	c.369+5A>G		splice_donor_5th_base_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AFP	ENST00000395792.7	c.843+5A>G		splice_donor_5th_base_variant, intron_variant		1	NM_001134.3	P1
AFP	ENST00000226359.2	c.843+5A>G		splice_donor_5th_base_variant, intron_variant		5

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

GnomAD3 exomes AF: 0.541 AC: 135915 AN: 251370 Hom.: 37490 AF XY: 0.544 AC XY: 73900 AN XY: 135870

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 SAS exome AF: 0.496

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

Gnomad4 AFR exome AF: 0.433

Gnomad4 AMR exome AF: 0.460

Gnomad4 ASJ exome AF: 0.447

Gnomad4 EAS exome AF: 0.667

Gnomad4 SAS exome AF: 0.501

Gnomad4 FIN exome AF: 0.548

Gnomad4 NFE exome AF: 0.576

Gnomad4 OTH exome AF: 0.540

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

Gnomad4 AFR AF: 0.438

Gnomad4 AMR AF: 0.457

Gnomad4 ASJ AF: 0.436

Gnomad4 EAS AF: 0.667

Gnomad4 SAS AF: 0.496

Gnomad4 FIN AF: 0.541

Gnomad4 NFE AF: 0.576

Gnomad4 OTH AF: 0.477

Alfa AF: 0.556 Hom.: 53817

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 v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	13
DANN	Benign	0.82

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

Publications

LitVar

Other links and lift over

dbSNP: rs2298839; hg19: chr4-74310844; COSMIC: COSV56924958;