4-73438185-T-G

Variant names:

• chr4-73438185-T-G
• NM_001134.3:c.149T>G

Variant summary

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

The NM_001354717.2(AFP):​c.-184T>G variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,180 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: AFP NM_001354717.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0980

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AFP	NM_001134.3	c.149T>G	p.Phe50Cys	missense_variant	Exon 3 of 15	ENST00000395792.7	NP_001125.1
AFP	NM_001354717.2	c.-184T>G		5_prime_UTR_premature_start_codon_gain_variant	Exon 3 of 16		NP_001341646.2
AFP	NM_001354717.2	c.-184T>G		5_prime_UTR_variant	Exon 3 of 16		NP_001341646.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AFP	ENST00000395792.7	c.149T>G	p.Phe50Cys	missense_variant	Exon 3 of 15	1	NM_001134.3	ENSP00000379138.2
AFP	ENST00000226359.2	c.149T>G	p.Phe50Cys	missense_variant	Exon 3 of 14	5		ENSP00000226359.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461180 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726892

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: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.18	T;T
Eigen	Benign	-0.20
Eigen_PC	Benign	-0.35
FATHMM_MKL	Benign	0.36	N
LIST_S2	Benign	0.71	T;T
M_CAP	Benign	0.0077	T
MetaRNN	Uncertain	0.52	D;D
MetaSVM	Benign	-0.99	T
MutationAssessor	Uncertain	2.4	M;.
PrimateAI	Benign	0.47	T
PROVEAN	Benign	0.010	N;N
REVEL	Benign	0.21
Sift	Benign	0.092	T;T
Sift4G	Benign	0.099	T;T
Polyphen		0.94	P;.
Vest4		0.60
MutPred		0.59		Gain of catalytic residue at F50 (P = 0.1688);Gain of catalytic residue at F50 (P = 0.1688);
MVP		0.69
MPC		0.29
ClinPred		0.96	D
GERP RS		1.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.2
Varity_R		0.31
gMVP		0.34

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: chr4-74303902;