20-3660176-C-T

Position:

• chr20-3660176-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP7 BA1

The NM_022139.4(GFRA4):​c.711G>A​(p.Pro237Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.495 in 1,591,766 control chromosomes in the GnomAD database, including 202,057 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.39 (13741 hom., cov: 33)
  • Exomes 𝑓: 0.51 (188316 hom.)
• Consequence: GFRA4 NM_022139.4 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0770

Genes affected

GFRA4 (HGNC:13821): (GDNF family receptor alpha 4) The protein encoded by this gene is a member of the GDNF receptor family. It is a glycosylphosphatidylinositol(GPI)-linked cell surface receptor for persephin, and mediates activation of the RET tyrosine kinase receptor. This gene is a candidate gene for RET-associated diseases. Alternatively spliced transcript variants encoding different isoforms have been described for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP7: Synonymous conserved (PhyloP=0.077 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.509 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GFRA4	NM_022139.4	c.711G>A	p.Pro237Pro	synonymous_variant	5/6	ENST00000290417.7	NP_071422.1
GFRA4	NM_145762.3	c.801G>A	p.Pro267Pro	synonymous_variant	4/5		NP_665705.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GFRA4	ENST00000290417.7	c.711G>A	p.Pro237Pro	synonymous_variant	5/6	1	NM_022139.4	ENSP00000290417.2
GFRA4	ENST00000319242.8	c.801G>A	p.Pro267Pro	synonymous_variant	4/5	1		ENSP00000313423.3

Frequencies

GnomAD3 genomes AF: 0.391 AC: 59322 AN: 151884 Hom.: 13738 Cov.: 33

Gnomad AFR AF: 0.129

Gnomad AMI AF: 0.530

Gnomad AMR AF: 0.480

Gnomad ASJ AF: 0.486

Gnomad EAS AF: 0.440

Gnomad SAS AF: 0.507

Gnomad FIN AF: 0.367

Gnomad MID AF: 0.414

Gnomad NFE AF: 0.514

Gnomad OTH AF: 0.405

GnomAD3 exomes AF: 0.467 AC: 101139 AN: 216660 Hom.: 24474 AF XY: 0.474 AC XY: 55858 AN XY: 117848

Gnomad AFR exome AF: 0.119

Gnomad AMR exome AF: 0.507

Gnomad ASJ exome AF: 0.481

Gnomad EAS exome AF: 0.434

Gnomad SAS exome AF: 0.501

Gnomad FIN exome AF: 0.375

Gnomad NFE exome AF: 0.514

Gnomad OTH exome AF: 0.484

GnomAD4 exome AF: 0.506 AC: 728286 AN: 1439764 Hom.: 188316 Cov.: 43 AF XY: 0.506 AC XY: 361400 AN XY: 714510

Gnomad4 AFR exome AF: 0.111

Gnomad4 AMR exome AF: 0.505

Gnomad4 ASJ exome AF: 0.480

Gnomad4 EAS exome AF: 0.457

Gnomad4 SAS exome AF: 0.495

Gnomad4 FIN exome AF: 0.378

Gnomad4 NFE exome AF: 0.528

Gnomad4 OTH exome AF: 0.483

GnomAD4 genome AF: 0.390 AC: 59347 AN: 152002 Hom.: 13741 Cov.: 33 AF XY: 0.388 AC XY: 28808 AN XY: 74302

Gnomad4 AFR AF: 0.129

Gnomad4 AMR AF: 0.480

Gnomad4 ASJ AF: 0.486

Gnomad4 EAS AF: 0.440

Gnomad4 SAS AF: 0.508

Gnomad4 FIN AF: 0.367

Gnomad4 NFE AF: 0.514

Gnomad4 OTH AF: 0.408

Alfa AF: 0.458 Hom.: 7432

Bravo AF: 0.389

Asia WGS AF: 0.477 AC: 1658 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	3.4
DANN	Benign	0.56

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: rs2853208; hg19: chr20-3640823; COSMIC: COSV51774907; COSMIC: COSV51774907;