4-73436434-A-T

Position:

• chr4-73436434-A-T

Variant summary

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

The NM_001134.3(AFP):​c.85+87A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.525 in 756,282 control chromosomes in the GnomAD database, including 105,281 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 0.52 (20654 hom., cov: 33)
  • Exomes 𝑓: 0.53 (84627 hom.)
• Consequence: AFP NM_001134.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.690

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.57 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AFP	NM_001134.3	c.85+87A>T		intron_variant		ENST00000395792.7	NP_001125.1
AFP	NM_001354717.2	c.-248+87A>T		intron_variant			NP_001341646.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AFP	ENST00000395792.7	c.85+87A>T		intron_variant		1	NM_001134.3	ENSP00000379138.2
AFP	ENST00000513720.5	n.147-726A>T		intron_variant		1
AFP	ENST00000515675.1	n.267-726A>T		intron_variant		1
AFP	ENST00000226359.2	c.85+87A>T		intron_variant		5		ENSP00000226359.2

Frequencies

GnomAD3 genomes AF: 0.517 AC: 78365 AN: 151476 Hom.: 20658 Cov.: 33

Gnomad AFR AF: 0.448

Gnomad AMI AF: 0.580

Gnomad AMR AF: 0.441

Gnomad ASJ AF: 0.441

Gnomad EAS AF: 0.566

Gnomad SAS AF: 0.515

Gnomad FIN AF: 0.529

Gnomad MID AF: 0.509

Gnomad NFE AF: 0.575

Gnomad OTH AF: 0.489

GnomAD4 exome AF: 0.527 AC: 318591 AN: 604688 Hom.: 84627 AF XY: 0.529 AC XY: 169210 AN XY: 319882

Gnomad4 AFR exome AF: 0.420

Gnomad4 AMR exome AF: 0.418

Gnomad4 ASJ exome AF: 0.438

Gnomad4 EAS exome AF: 0.537

Gnomad4 SAS exome AF: 0.510

Gnomad4 FIN exome AF: 0.532

Gnomad4 NFE exome AF: 0.542

Gnomad4 OTH exome AF: 0.510

GnomAD4 genome AF: 0.517 AC: 78372 AN: 151594 Hom.: 20654 Cov.: 33 AF XY: 0.513 AC XY: 37999 AN XY: 74066

Gnomad4 AFR AF: 0.448

Gnomad4 AMR AF: 0.441

Gnomad4 ASJ AF: 0.441

Gnomad4 EAS AF: 0.566

Gnomad4 SAS AF: 0.515

Gnomad4 FIN AF: 0.529

Gnomad4 NFE AF: 0.575

Gnomad4 OTH AF: 0.484

Alfa AF: 0.542 Hom.: 2687

Bravo AF: 0.508

Asia WGS AF: 0.470 AC: 1610 AN: 3430

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.34
DANN	Benign	0.72

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: rs3796677; hg19: chr4-74302151; COSMIC: COSV56926774;