rs3796678

chr4-73436354-T-Achr4-73436354-T-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

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. Variant has been reported in Lovd as Benign (no stars).

• 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

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 Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.65).
• BP6: Variant 4-73436354-T-A is Benign according to our data. Variant chr4-73436354-T-A is described in Lovd as [Benign].
• 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/exons	MANE	UniProt
AFP	NM_001134.3	c.85+7T>A		splice_region_variant, intron_variant		ENST00000395792.7
AFP	NM_001354717.2	c.-248+7T>A		splice_region_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AFP	ENST00000395792.7	c.85+7T>A		splice_region_variant, intron_variant		1	NM_001134.3	P1
AFP	ENST00000513720.5	n.147-806T>A		intron_variant, non_coding_transcript_variant		1
AFP	ENST00000515675.1	n.267-806T>A		intron_variant, non_coding_transcript_variant		1
AFP	ENST00000226359.2	c.85+7T>A		splice_region_variant, intron_variant		5

Frequencies

GnomAD3 genomes AF: 0.517 AC: 78358 AN: 151526 Hom.: 20642 Cov.: 33

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

GnomAD3 exomes AF: 0.523 AC: 119278 AN: 227958 Hom.: 31854 AF XY: 0.530 AC XY: 65494 AN XY: 123680

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 SAS exome AF: 0.506

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.: 21 AF XY: 0.552 AC XY: 372967 AN XY: 676148

Gnomad4 AFR exome AF: 0.432

Gnomad4 AMR exome AF: 0.407

Gnomad4 ASJ exome AF: 0.446

Gnomad4 EAS exome AF: 0.544

Gnomad4 SAS exome AF: 0.508

Gnomad4 FIN exome AF: 0.535

Gnomad4 NFE exome AF: 0.568

Gnomad4 OTH exome AF: 0.527

GnomAD4 genome AF: 0.517 AC: 78365 AN: 151644 Hom.: 20638 Cov.: 33 AF XY: 0.513 AC XY: 37998 AN XY: 74092

Gnomad4 AFR AF: 0.447

Gnomad4 AMR AF: 0.441

Gnomad4 ASJ AF: 0.441

Gnomad4 EAS AF: 0.567

Gnomad4 SAS AF: 0.515

Gnomad4 FIN AF: 0.529

Gnomad4 NFE AF: 0.575

Gnomad4 OTH AF: 0.482

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	10
Dann	Benign	0.80

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

LitVar

Other links and lift over

dbSNP: rs3796678; hg19: chr4-74302071; COSMIC: COSV56924998;