chr4-73447550-G-A

Position:

• chr4-73447550-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001134.3(AFP):​c.932G>A​(p.Gly311Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,460,640 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: AFP NM_001134.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.19

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.888

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AFP	NM_001134.3	c.932G>A	p.Gly311Asp	missense_variant	8/15	ENST00000395792.7
AFP	NM_001354717.2	c.458G>A	p.Gly153Asp	missense_variant	9/16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AFP	ENST00000395792.7	c.932G>A	p.Gly311Asp	missense_variant	8/15	1	NM_001134.3	P1
AFP	ENST00000226359.2	c.932G>A	p.Gly311Asp	missense_variant	8/14	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1460640 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 726656

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.0000166

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

May 11, 2022

The c.932G>A (p.G311D) alteration is located in exon 8 (coding exon 8) of the AFP gene. This alteration results from a G to A substitution at nucleotide position 932, causing the glycine (G) at amino acid position 311 to be replaced by an aspartic acid (D). 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	Uncertain	0.54
BayesDel_addAF	Uncertain	0.080	D
BayesDel_noAF	Benign	-0.12
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Benign	0.27	T;T
Eigen	Benign	-0.068
Eigen_PC	Benign	-0.28
FATHMM_MKL	Benign	0.28	N
LIST_S2	Benign	0.77	T;T
M_CAP	Benign	0.080	D
MetaRNN	Pathogenic	0.89	D;D
MetaSVM	Benign	-0.35	T
MutationAssessor	Uncertain	2.7	M;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.46	T
PROVEAN	Uncertain	-3.7	D;D
REVEL	Uncertain	0.45
Sift	Uncertain	0.0030	D;D
Sift4G	Uncertain	0.0070	D;D
Polyphen		1.0	D;.
Vest4		0.61
MutPred		0.77		Gain of catalytic residue at G311 (P = 0.0651);Gain of catalytic residue at G311 (P = 0.0651);
MVP		0.85
MPC		0.31
ClinPred		0.91	D
GERP RS		2.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.52
gMVP		0.47

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: chr4-74313267;