4-73436434-A-T

Variant names:

• chr4-73436434-A-T
• rs3796677
• NM_001134.3:c.85+87A>T

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 5 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=-0.9).
• 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 rank	MANE	Protein	UniProt
AFP	NM_001134.3	c.85+87A>T		intron_variant	Intron 1 of 14	ENST00000395792.7	NP_001125.1
AFP	NM_001354717.2	c.-248+87A>T		intron_variant	Intron 1 of 15		NP_001341646.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AFP	ENST00000395792.7	c.85+87A>T		intron_variant	Intron 1 of 14	1	NM_001134.3	ENSP00000379138.2
AFP	ENST00000513720.5	n.147-726A>T		intron_variant	Intron 1 of 1	1
AFP	ENST00000515675.1	n.267-726A>T		intron_variant	Intron 2 of 2	1
AFP	ENST00000226359.2	c.85+87A>T		intron_variant	Intron 1 of 13	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

African (AFR) AF: 0.420 AC: 6047 AN: 14394

American (AMR) AF: 0.418 AC: 7870 AN: 18826

Ashkenazi Jewish (ASJ) AF: 0.438 AC: 7355 AN: 16788

East Asian (EAS) AF: 0.537 AC: 16252 AN: 30262

South Asian (SAS) AF: 0.510 AC: 24811 AN: 48648

European-Finnish (FIN) AF: 0.532 AC: 22810 AN: 42884

Middle Eastern (MID) AF: 0.476 AC: 1067 AN: 2240

European-Non Finnish (NFE) AF: 0.542 AC: 217042 AN: 400596

Other (OTH) AF: 0.510 AC: 15337 AN: 30050

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

African (AFR) AF: 0.448 AC: 18546 AN: 41422

American (AMR) AF: 0.441 AC: 6712 AN: 15218

Ashkenazi Jewish (ASJ) AF: 0.441 AC: 1527 AN: 3460

East Asian (EAS) AF: 0.566 AC: 2931 AN: 5174

South Asian (SAS) AF: 0.515 AC: 2482 AN: 4822

European-Finnish (FIN) AF: 0.529 AC: 5528 AN: 10448

Middle Eastern (MID) AF: 0.507 AC: 149 AN: 294

European-Non Finnish (NFE) AF: 0.575 AC: 38952 AN: 67742

Other (OTH) AF: 0.484 AC: 1021 AN: 2110

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
PhyloP100		-0.69
PromoterAI		0.0070	Neutral
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: rs3796677; hg19: chr4-74302151; COSMIC: COSV56926774;