rs3796678

Variant names:

• chr4-73436354-T-A
• rs3796678
• NM_001134.3:c.85+7T>A

Your query was ambiguous. Multiple possible variants found:

• chr4-73436354-T-A
• chr4-73436354-T-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.85+7T>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.548 in 1,506,510 control chromosomes in the GnomAD database, including 228,656 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.52 (20638 hom., cov: 33)
  • Exomes 𝑓: 0.55 (208018 hom.)
• Consequence: AFP NM_001134.3 splice_region, intron
• Scores: Splicing: ADA: 0.002615
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.30
• Publications: 13 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=-0.65).
• 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+7T>A		splice_region_variant, intron_variant	Intron 1 of 14	ENST00000395792.7	NP_001125.1
AFP	NM_001354717.2	c.-248+7T>A		splice_region_variant, 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+7T>A		splice_region_variant, intron_variant	Intron 1 of 14	1	NM_001134.3	ENSP00000379138.2
AFP	ENST00000513720.5	n.147-806T>A		intron_variant	Intron 1 of 1	1
AFP	ENST00000515675.1	n.267-806T>A		intron_variant	Intron 2 of 2	1
AFP	ENST00000226359.2	c.85+7T>A		splice_region_variant, intron_variant	Intron 1 of 13	5		ENSP00000226359.2

Frequencies

GnomAD3 genomes AF: 0.517 AC: 78358 AN: 151526 Hom.: 20642 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: 0.488

GnomAD2 exomes AF: 0.523 AC: 119278 AN: 227958 AF XY: 0.530

Gnomad AFR exome AF: 0.442

Gnomad AMR exome AF: 0.399

Gnomad ASJ exome AF: 0.449

Gnomad EAS exome AF: 0.579

Gnomad FIN exome AF: 0.531

Gnomad NFE exome AF: 0.570

Gnomad OTH exome AF: 0.519

GnomAD4 exome AF: 0.551 AC: 746486 AN: 1354866 Hom.: 208018 Cov.: 21 AF XY: 0.552 AC XY: 372967 AN XY: 676148

African (AFR) AF: 0.432 AC: 13316 AN: 30820

American (AMR) AF: 0.407 AC: 16321 AN: 40132

Ashkenazi Jewish (ASJ) AF: 0.446 AC: 11026 AN: 24708

East Asian (EAS) AF: 0.544 AC: 20599 AN: 37844

South Asian (SAS) AF: 0.508 AC: 38124 AN: 75010

European-Finnish (FIN) AF: 0.535 AC: 27757 AN: 51852

Middle Eastern (MID) AF: 0.478 AC: 2433 AN: 5092

European-Non Finnish (NFE) AF: 0.568 AC: 587310 AN: 1033288

Other (OTH) AF: 0.527 AC: 29600 AN: 56120

GnomAD4 genome AF: 0.517 AC: 78365 AN: 151644 Hom.: 20638 Cov.: 33 AF XY: 0.513 AC XY: 37998 AN XY: 74092

African (AFR) AF: 0.447 AC: 18530 AN: 41458

American (AMR) AF: 0.441 AC: 6703 AN: 15214

Ashkenazi Jewish (ASJ) AF: 0.441 AC: 1529 AN: 3466

East Asian (EAS) AF: 0.567 AC: 2926 AN: 5162

South Asian (SAS) AF: 0.515 AC: 2486 AN: 4826

European-Finnish (FIN) AF: 0.529 AC: 5566 AN: 10514

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

European-Non Finnish (NFE) AF: 0.575 AC: 38936 AN: 67700

Other (OTH) AF: 0.482 AC: 1017 AN: 2108

Alfa AF: 0.548 Hom.: 7512

Bravo AF: 0.508

Asia WGS AF: 0.468 AC: 1620 AN: 3460

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.65
CADD	Benign	10
DANN	Benign	0.80
PhyloP100		1.3
PromoterAI		0.0053	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0026
dbscSNV1_RF	Benign	0.012
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: rs3796678; hg19: chr4-74302071; COSMIC: COSV56924998;