4-73453566-T-G

Position:

• chr4-73453566-T-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001134.3(AFP):​c.1653-199T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.422 in 616,360 control chromosomes in the GnomAD database, including 56,057 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 0.43 (14229 hom., cov: 32)
  • Exomes 𝑓: 0.42 (41828 hom.)
• Consequence: AFP NM_001134.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.341

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.505 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AFP	NM_001134.3	c.1653-199T>G		intron_variant		ENST00000395792.7
AFP	NM_001354717.2	c.1179-199T>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AFP	ENST00000395792.7	c.1653-199T>G		intron_variant		1	NM_001134.3	P1

Frequencies

GnomAD3 genomes AF: 0.428 AC: 65024 AN: 151936 Hom.: 14195 Cov.: 32

Gnomad AFR AF: 0.439

Gnomad AMI AF: 0.390

Gnomad AMR AF: 0.514

Gnomad ASJ AF: 0.552

Gnomad EAS AF: 0.340

Gnomad SAS AF: 0.474

Gnomad FIN AF: 0.428

Gnomad MID AF: 0.481

Gnomad NFE AF: 0.398

Gnomad OTH AF: 0.471

GnomAD4 exome AF: 0.421 AC: 195262 AN: 464306 Hom.: 41828 Cov.: 6 AF XY: 0.421 AC XY: 103287 AN XY: 245244

Gnomad4 AFR exome AF: 0.440

Gnomad4 AMR exome AF: 0.521

Gnomad4 ASJ exome AF: 0.547

Gnomad4 EAS exome AF: 0.343

Gnomad4 SAS exome AF: 0.464

Gnomad4 FIN exome AF: 0.422

Gnomad4 NFE exome AF: 0.404

Gnomad4 OTH exome AF: 0.443

GnomAD4 genome AF: 0.428 AC: 65123 AN: 152054 Hom.: 14229 Cov.: 32 AF XY: 0.432 AC XY: 32133 AN XY: 74336

Gnomad4 AFR AF: 0.440

Gnomad4 AMR AF: 0.514

Gnomad4 ASJ AF: 0.552

Gnomad4 EAS AF: 0.340

Gnomad4 SAS AF: 0.474

Gnomad4 FIN AF: 0.428

Gnomad4 NFE AF: 0.398

Gnomad4 OTH AF: 0.477

Alfa AF: 0.369 Hom.: 3081

Bravo AF: 0.434

Asia WGS AF: 0.452 AC: 1572 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	2.0
DANN	Benign	0.62

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

Publications

LitVar

Other links and lift over

dbSNP: rs12506899; hg19: chr4-74319283;