Genetic Variant AFP:p.Thr132Ser (chr4-73440725-A-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001134.3(AFP):c.394A>T(p.Thr132Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,882 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T132P) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

AFP
NM_001134.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.771

Publications

1 publications found

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 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

AFP links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.03403181).

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.394A>T	p.Thr132Ser	missense	Exon 4 of 15	NP_001125.1	P02771
	AFP	NM_001354717.2		c.-5+66A>T		intron	N/A	NP_001341646.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AFP	ENST00000395792.7	TSL:1 MANE Select	c.394A>T	p.Thr132Ser	missense	Exon 4 of 15	ENSP00000379138.2	P02771
	AFP	ENST00000226359.2	TSL:5	c.394A>T	p.Thr132Ser	missense	Exon 4 of 14	ENSP00000226359.2	J3KMX3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000398

AC:

AN:

251456

AF XY:

0.00000736

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461882

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727238

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39694

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1112008

Other (OTH)

AF:

0.00

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.072

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.79

CADD

Benign

0.14

(source)

DANN

Benign

0.50

DEOGEN2

Benign

0.057

Eigen

Benign

-1.7

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.12

LIST_S2

Benign

0.46

M_CAP

Benign

0.0034

MetaRNN

Benign

0.034

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.23

PhyloP100

-0.77

PrimateAI

Benign

0.27

PROVEAN

Benign

0.71

REVEL

Benign

0.010

Sift

Benign

0.90

Sift4G

Benign

1.0

Polyphen

0.0010

Vest4

0.077

MutPred

0.44

Gain of glycosylation at T132 (P = 0.0273)

MVP

0.23

MPC

0.040

ClinPred

0.18

GERP RS

-2.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.036

gMVP

0.052

Mutation Taster

=96/4

polymorphism

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over