chr4-73440656-G-C

Variant names:

• chr4-73440656-G-C
• rs115932512
• NM_001134.3:c.325G>C

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_001134.3(AFP):​c.325G>C​(p.Gly109Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000365 in 1,614,140 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0017 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00022 (2 hom.)
• Consequence: AFP NM_001134.3 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.79

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

Our verdict: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.006657034).
• BP6: Variant 4-73440656-G-C is Benign according to our data. Variant chr4-73440656-G-C is described in ClinVar as [Benign]. Clinvar id is 742527.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd4 at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AFP	NM_001134.3	c.325G>C	p.Gly109Arg	missense_variant	Exon 4 of 15	ENST00000395792.7	NP_001125.1
AFP	NM_001354717.2	c.-8G>C		5_prime_UTR_variant	Exon 4 of 16		NP_001341646.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AFP	ENST00000395792.7	c.325G>C	p.Gly109Arg	missense_variant	Exon 4 of 15	1	NM_001134.3	ENSP00000379138.2
AFP	ENST00000226359.2	c.325G>C	p.Gly109Arg	missense_variant	Exon 4 of 14	5		ENSP00000226359.2

Frequencies

GnomAD3 genomes AF: 0.00172 AC: 261 AN: 152146 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00620

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.000549 AC: 138 AN: 251488 AF XY: 0.000390

Gnomad AFR exome AF: 0.00812

Gnomad AMR exome AF: 0.0000867

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: 0.000326

GnomAD4 exome AF: 0.000224 AC: 328 AN: 1461876 Hom.: 2 Cov.: 31 AF XY: 0.000204 AC XY: 148 AN XY: 727236

Gnomad4 AFR exome AF: 0.00824 AC: 276 AN: 33480

Gnomad4 AMR exome AF: 0.000201 AC: 9 AN: 44724

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 26134

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 39696

Gnomad4 SAS exome AF: 0.00 AC: 0 AN: 86254

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 53420

Gnomad4 NFE exome AF: 0.0000135 AC: 15 AN: 1112006

Gnomad4 Remaining exome AF: 0.000464 AC: 28 AN: 60394

GnomAD4 genome AF: 0.00171 AC: 261 AN: 152264 Hom.: 2 Cov.: 32 AF XY: 0.00161 AC XY: 120 AN XY: 74452

Gnomad4 AFR AF: 0.00619 AC: 0.00618532 AN: 0.00618532

Gnomad4 AMR AF: 0.000131 AC: 0.000130719 AN: 0.000130719

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.00 AC: 0 AN: 0

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.0000147 AC: 0.0000147007 AN: 0.0000147007

Gnomad4 OTH AF: 0.000474 AC: 0.000473934 AN: 0.000473934

Alfa AF: 0.000127 Hom.: 0

Bravo AF: 0.00214

ESP6500AA AF: 0.00794 AC: 35

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000675 AC: 82

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Aug 16, 2018

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
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.20
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.30	T;T
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.75	T;T
MetaRNN	Benign	0.0067	T;T
MetaSVM	Benign	-0.51	T
MutationAssessor	Uncertain	2.7	M;.
PrimateAI	Benign	0.44	T
PROVEAN	Pathogenic	-5.1	D;D
REVEL	Uncertain	0.32
Sift	Uncertain	0.0030	D;D
Sift4G	Uncertain	0.015	D;D
Polyphen		1.0	D;.
Vest4		0.49
MutPred		0.50		Gain of glycosylation at S111 (P = 0.0575);Gain of glycosylation at S111 (P = 0.0575);
MVP		0.89
MPC		0.31
ClinPred		0.081	T
GERP RS		3.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.62
gMVP		0.20
Mutation Taster		=96/4	polymorphism

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

LitVar

Other links and lift over

dbSNP: rs115932512; hg19: chr4-74306373;