Genetic Variant AFP:c.85+7T>A (chr4-73436354-T-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_001134.3(AFP):c.85+7T>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.548 in 1,506,510 control chromosomes in the GnomAD database, including 228,656 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.52 ( 20638 hom., cov: 33)

Exomes 𝑓: 0.55 ( 208018 hom. )

Consequence

AFP
NM_001134.3 splice_region, intron

Scores

Splicing: ADA: 0.002615

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.30

Publications

13 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: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.65).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.57 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AFP	NM_001134.3 link	c.85+7T>A		splice_region_variant, intron_variant	Intron 1 of 14	ENST00000395792.7	NP_001125.1
AFP	NM_001354717.2 link	c.-248+7T>A		splice_region_variant, intron_variant	Intron 1 of 15		NP_001341646.2

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein
AFP	ENST00000395792.7 link	c.85+7T>A	splice_region_variant, intron_variant	Intron 1 of 14	1	NM_001134.3	ENSP00000379138.2
AFP	ENST00000513720.5 link	n.147-806T>A	intron_variant	Intron 1 of 1	1
AFP	ENST00000515675.1 link	n.267-806T>A	intron_variant	Intron 2 of 2	1
AFP	ENST00000226359.2 link	c.85+7T>A	splice_region_variant, intron_variant	Intron 1 of 13	5		ENSP00000226359.2

Frequencies

GnomAD3 genomes

AF:

0.517

AC:

78358

AN:

151526

Hom.:

20642

Cov.:

show subpopulations

Gnomad AFR

AF:

0.448

Gnomad AMI

AF:

0.580

Gnomad AMR

AF:

0.441

Gnomad ASJ

AF:

0.441

Gnomad EAS

AF:

0.566

Gnomad SAS

AF:

0.515

Gnomad FIN

AF:

0.529

Gnomad MID

AF:

0.509

Gnomad NFE

AF:

0.575

Gnomad OTH

AF:

0.488

GnomAD2 exomes

AF:

0.523

AC:

119278

AN:

227958

AF XY:

0.530

show subpopulations

Gnomad AFR exome

AF:

0.442

Gnomad AMR exome

AF:

0.399

Gnomad ASJ exome

AF:

0.449

Gnomad EAS exome

AF:

0.579

Gnomad FIN exome

AF:

0.531

Gnomad NFE exome

AF:

0.570

Gnomad OTH exome

AF:

0.519

GnomAD4 exome

AF:

0.551

AC:

746486

AN:

1354866

Hom.:

208018

Cov.:

AF XY:

0.552

AC XY:

372967

AN XY:

676148

show subpopulations

African (AFR)

AF:

0.432

AC:

13316

AN:

30820

American (AMR)

AF:

0.407

AC:

16321

AN:

40132

Ashkenazi Jewish (ASJ)

AF:

0.446

AC:

11026

AN:

24708

East Asian (EAS)

AF:

0.544

AC:

20599

AN:

37844

South Asian (SAS)

AF:

0.508

AC:

38124

AN:

75010

European-Finnish (FIN)

AF:

0.535

AC:

27757

AN:

51852

Middle Eastern (MID)

AF:

0.478

AC:

2433

AN:

5092

European-Non Finnish (NFE)

AF:

0.568

AC:

587310

AN:

1033288

Other (OTH)

AF:

0.527

AC:

29600

AN:

56120

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.454

Heterozygous variant carriers

13225

26450

39676

52901

66126

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

16152

32304

48456

64608

80760

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.517

AC:

78365

AN:

151644

Hom.:

20638

Cov.:

AF XY:

0.513

AC XY:

37998

AN XY:

74092

show subpopulations

African (AFR)

AF:

0.447

AC:

18530

AN:

41458

American (AMR)

AF:

0.441

AC:

6703

AN:

15214

Ashkenazi Jewish (ASJ)

AF:

0.441

AC:

1529

AN:

3466

East Asian (EAS)

AF:

0.567

AC:

2926

AN:

5162

South Asian (SAS)

AF:

0.515

AC:

2486

AN:

4826

European-Finnish (FIN)

AF:

0.529

AC:

5566

AN:

10514

Middle Eastern (MID)

AF:

0.507

AC:

149

AN:

294

European-Non Finnish (NFE)

AF:

0.575

AC:

38936

AN:

67700

Other (OTH)

AF:

0.482

AC:

1017

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1926

3852

5778

7704

9630

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

708

1416

2124

2832

3540

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.548

Hom.:

7512

Bravo

AF:

0.508

Asia WGS

AF:

0.468

AC:

1620

AN:

3460

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.65

CADD

Benign

(source)

DANN

Benign

0.80

PhyloP100

1.3

PromoterAI

0.0053

Neutral

(source)

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0026

dbscSNV1_RF

Benign

0.012

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over