chr4-73447476-C-T

Variant names:

• chr4-73447476-C-T
• rs28482344
• NM_001134.3:c.858C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001134.3(AFP):​c.858C>T​(p.Ser286Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0143 in 1,608,108 control chromosomes in the GnomAD database, including 210 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0090 (10 hom., cov: 32)
  • Exomes 𝑓: 0.015 (200 hom.)
• Consequence: AFP NM_001134.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.17
• Publications: 2 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.6).
• BP6: Variant 4-73447476-C-T is Benign according to our data. Variant chr4-73447476-C-T is described in ClinVar as Benign. ClinVar VariationId is 771142.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.0149 (21636/1456054) while in subpopulation NFE AF = 0.0179 (19847/1108956). AF 95% confidence interval is 0.0177. There are 200 homozygotes in GnomAdExome4. There are 10425 alleles in the male GnomAdExome4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 10 AD,AR gene

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AFP	NM_001134.3	MANE Select	c.858C>T	p.Ser286Ser	synonymous	Exon 8 of 15	NP_001125.1	P02771
	AFP	NM_001354717.2		c.384C>T	p.Ser128Ser	synonymous	Exon 9 of 16	NP_001341646.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AFP	ENST00000395792.7	TSL:1 MANE Select	c.858C>T	p.Ser286Ser	synonymous	Exon 8 of 15	ENSP00000379138.2	P02771
	AFP	ENST00000226359.2	TSL:5	c.858C>T	p.Ser286Ser	synonymous	Exon 8 of 14	ENSP00000226359.2	J3KMX3

Frequencies

GnomAD3 genomes AF: 0.00905 AC: 1375 AN: 151936 Hom.: 10 Cov.: 32

Gnomad AFR AF: 0.00334

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00603

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00332

Gnomad FIN AF: 0.00396

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0155

Gnomad OTH AF: 0.00960

GnomAD2 exomes AF: 0.00872 AC: 2163 AN: 248124 AF XY: 0.00829

Gnomad AFR exome AF: 0.00287

Gnomad AMR exome AF: 0.00664

Gnomad ASJ exome AF: 0.00131

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00464

Gnomad NFE exome AF: 0.0146

Gnomad OTH exome AF: 0.00976

GnomAD4 exome AF: 0.0149 AC: 21636 AN: 1456054 Hom.: 200 Cov.: 32 AF XY: 0.0144 AC XY: 10425 AN XY: 724464

African (AFR) AF: 0.00253 AC: 84 AN: 33222

American (AMR) AF: 0.00679 AC: 300 AN: 44194

Ashkenazi Jewish (ASJ) AF: 0.00181 AC: 47 AN: 26018

East Asian (EAS) AF: 0.0000757 AC: 3 AN: 39644

South Asian (SAS) AF: 0.00338 AC: 289 AN: 85608

European-Finnish (FIN) AF: 0.00453 AC: 241 AN: 53220

Middle Eastern (MID) AF: 0.00773 AC: 39 AN: 5048

European-Non Finnish (NFE) AF: 0.0179 AC: 19847 AN: 1108956

Other (OTH) AF: 0.0131 AC: 786 AN: 60144

GnomAD4 genome AF: 0.00904 AC: 1375 AN: 152054 Hom.: 10 Cov.: 32 AF XY: 0.00830 AC XY: 617 AN XY: 74370

African (AFR) AF: 0.00333 AC: 138 AN: 41476

American (AMR) AF: 0.00602 AC: 92 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00173 AC: 6 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00332 AC: 16 AN: 4816

European-Finnish (FIN) AF: 0.00396 AC: 42 AN: 10596

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.0155 AC: 1055 AN: 67932

Other (OTH) AF: 0.00950 AC: 20 AN: 2106

Alfa AF: 0.0144 Hom.: 25

Bravo AF: 0.00954

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.0150

EpiControl AF: 0.0135

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.60
CADD	Benign	3.0
DANN	Benign	0.67
PhyloP100		-1.2
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs28482344; hg19: chr4-74313193;