Genetic Variant AFP:p.Ser286Ser (chr4-73447476-C-T) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -1.17

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 id 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. gnomad4_exome 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 gnomad4_exome. There are 10425 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 10 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AFP	NM_001134.3 link	c.858C>T	p.Ser286Ser	synonymous_variant	Exon 8 of 15	ENST00000395792.7	NP_001125.1	P02771
AFP	NM_001354717.2 link	c.384C>T	p.Ser128Ser	synonymous_variant	Exon 9 of 16		NP_001341646.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AFP	ENST00000395792.7 link	c.858C>T	p.Ser286Ser	synonymous_variant	Exon 8 of 15	1	NM_001134.3	ENSP00000379138.2		P02771
AFP	ENST00000226359.2 link	c.858C>T	p.Ser286Ser	synonymous_variant	Exon 8 of 14	5		ENSP00000226359.2		J3KMX3

Frequencies

GnomAD3 genomes

AF:

0.00905

AC:

1375

AN:

151936

Hom.:

Cov.:

show subpopulations

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

GnomAD3 exomes

AF:

0.00872

AC:

2163

AN:

248124

Hom.:

AF XY:

0.00829

AC XY:

1113

AN XY:

134336

show subpopulations

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 SAS exome

AF:

0.00282

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.:

AF XY:

0.0144

AC XY:

10425

AN XY:

724464

show subpopulations

Gnomad4 AFR exome

AF:

0.00253

Gnomad4 AMR exome

AF:

0.00679

Gnomad4 ASJ exome

AF:

0.00181

Gnomad4 EAS exome

AF:

0.0000757

Gnomad4 SAS exome

AF:

0.00338

Gnomad4 FIN exome

AF:

0.00453

Gnomad4 NFE exome

AF:

0.0179

Gnomad4 OTH exome

AF:

0.0131

GnomAD4 genome

AF:

0.00904

AC:

1375

AN:

152054

Hom.:

Cov.:

AF XY:

0.00830

AC XY:

617

AN XY:

74370

show subpopulations

Gnomad4 AFR

AF:

0.00333

Gnomad4 AMR

AF:

0.00602

Gnomad4 ASJ

AF:

0.00173

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00332

Gnomad4 FIN

AF:

0.00396

Gnomad4 NFE

AF:

0.0155

Gnomad4 OTH

AF:

0.00950

Alfa

AF:

0.0143

Hom.:

Bravo

AF:

0.00954

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.0150

EpiControl

AF:

0.0135

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.60

CADD

Benign

3.0

DANN

Benign

0.67

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over