4-73440725-A-C

Position:

• chr4-73440725-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001134.3(AFP):​c.394A>C​(p.Thr132Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: AFP NM_001134.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.771

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.089172155).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AFP	NM_001134.3	c.394A>C	p.Thr132Pro	missense_variant	4/15	ENST00000395792.7	NP_001125.1
AFP	NM_001354717.2	c.-5+66A>C		intron_variant			NP_001341646.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AFP	ENST00000395792.7	c.394A>C	p.Thr132Pro	missense_variant	4/15	1	NM_001134.3	ENSP00000379138.2
AFP	ENST00000226359.2	c.394A>C	p.Thr132Pro	missense_variant	4/14	5		ENSP00000226359.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 28, 2023

The c.394A>C (p.T132P) alteration is located in exon 4 (coding exon 4) of the AFP gene. This alteration results from a A to C substitution at nucleotide position 394, causing the threonine (T) at amino acid position 132 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	10
DANN	Benign	0.57
DEOGEN2	Benign	0.14	T;T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.57	T;T
M_CAP	Benign	0.0051	T
MetaRNN	Benign	0.089	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	L;.
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-1.1	N;N
REVEL	Benign	0.014
Sift	Benign	0.28	T;T
Sift4G	Benign	0.21	T;T
Polyphen		0.52	P;.
Vest4		0.16
MutPred		0.48		Gain of catalytic residue at P131 (P = 0.0207);Gain of catalytic residue at P131 (P = 0.0207);
MVP		0.23
MPC		0.10
ClinPred		0.65	D
GERP RS		-2.4
Varity_R		0.32
gMVP		0.19

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr4-74306442;