4-73453566-T-G

Variant names:

• chr4-73453566-T-G
• rs12506899
• NM_001134.3:c.1653-199T>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.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
• Publications: 16 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=-0.82).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.505 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AFP	NM_001134.3	MANE Select	c.1653-199T>G		intron	N/A	NP_001125.1
	AFP	NM_001354717.2		c.1179-199T>G		intron	N/A	NP_001341646.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AFP	ENST00000395792.7	TSL:1 MANE Select	c.1653-199T>G		intron	N/A	ENSP00000379138.2
	AFP	ENST00000506820.1	TSL:2	n.77T>G		non_coding_transcript_exon	Exon 1 of 4
	AFP	ENST00000226359.2	TSL:5	c.1653-199T>G		intron	N/A	ENSP00000226359.2

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

African (AFR) AF: 0.440 AC: 5562 AN: 12646

American (AMR) AF: 0.521 AC: 11548 AN: 22164

Ashkenazi Jewish (ASJ) AF: 0.547 AC: 7492 AN: 13696

East Asian (EAS) AF: 0.343 AC: 9861 AN: 28742

South Asian (SAS) AF: 0.464 AC: 21665 AN: 46736

European-Finnish (FIN) AF: 0.422 AC: 11871 AN: 28144

Middle Eastern (MID) AF: 0.514 AC: 988 AN: 1924

European-Non Finnish (NFE) AF: 0.404 AC: 114942 AN: 284680

Other (OTH) AF: 0.443 AC: 11333 AN: 25574

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

African (AFR) AF: 0.440 AC: 18255 AN: 41474

American (AMR) AF: 0.514 AC: 7853 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.552 AC: 1918 AN: 3472

East Asian (EAS) AF: 0.340 AC: 1761 AN: 5172

South Asian (SAS) AF: 0.474 AC: 2283 AN: 4812

European-Finnish (FIN) AF: 0.428 AC: 4528 AN: 10570

Middle Eastern (MID) AF: 0.483 AC: 141 AN: 292

European-Non Finnish (NFE) AF: 0.398 AC: 27023 AN: 67970

Other (OTH) AF: 0.477 AC: 1008 AN: 2114

Alfa AF: 0.402 Hom.: 22856

Bravo AF: 0.434

Asia WGS AF: 0.452 AC: 1572 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	2.0
DANN	Benign	0.62
PhyloP100		-0.34
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs12506899; hg19: chr4-74319283;