4-73436824-T-C

Position:

• chr4-73436824-T-C

Variant summary

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

The NM_001134.3(AFP):​c.86-336T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.464 in 151,584 control chromosomes in the GnomAD database, including 16,606 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 (16606 hom., cov: 31)
• Consequence: AFP NM_001134.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.181

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=-0.87).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.537 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AFP	NM_001134.3	c.86-336T>C		intron_variant		ENST00000395792.7
AFP	NM_001354717.2	c.-247-336T>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AFP	ENST00000395792.7	c.86-336T>C		intron_variant		1	NM_001134.3	P1
AFP	ENST00000513720.5	n.147-336T>C		intron_variant, non_coding_transcript_variant		1
AFP	ENST00000515675.1	n.267-336T>C		intron_variant, non_coding_transcript_variant		1
AFP	ENST00000226359.2	c.86-336T>C		intron_variant		5

Frequencies

GnomAD3 genomes AF: 0.464 AC: 70225 AN: 151466 Hom.: 16575 Cov.: 31

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: 0.471

Gnomad MID AF: 0.484

Gnomad NFE AF: 0.424

Gnomad OTH AF: 0.490

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.464 AC: 70317 AN: 151584 Hom.: 16606 Cov.: 31 AF XY: 0.468 AC XY: 34698 AN XY: 74096

Gnomad4 AFR AF: 0.490

Gnomad4 AMR AF: 0.547

Gnomad4 ASJ AF: 0.558

Gnomad4 EAS AF: 0.433

Gnomad4 SAS AF: 0.476

Gnomad4 FIN AF: 0.471

Gnomad4 NFE AF: 0.424

Gnomad4 OTH AF: 0.493

Alfa AF: 0.275 Hom.: 592

Bravo AF: 0.470

Asia WGS AF: 0.507 AC: 1761 AN: 3470

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	3.0
DANN	Benign	0.49

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: rs28532518; hg19: chr4-74302541;