20-3660176-C-T

Variant names:

• chr20-3660176-C-T
• rs2853208
• NM_022139.4:c.711G>A

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 13 publications found

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

Our verdict: Benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_022139.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GFRA4	NM_022139.4	MANE Select	c.711G>A	p.Pro237Pro	synonymous	Exon 5 of 6	NP_071422.1	Q9GZZ7-2
	GFRA4	NM_145762.3		c.801G>A	p.Pro267Pro	synonymous	Exon 4 of 5	NP_665705.1	Q9GZZ7-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GFRA4	ENST00000290417.7	TSL:1 MANE Select	c.711G>A	p.Pro237Pro	synonymous	Exon 5 of 6	ENSP00000290417.2	Q9GZZ7-2
	GFRA4	ENST00000319242.8	TSL:1	c.801G>A	p.Pro267Pro	synonymous	Exon 4 of 5	ENSP00000313423.3	Q9GZZ7-1
	GFRA4	ENST00000850978.1		c.453G>A	p.Pro151Pro	synonymous	Exon 5 of 6	ENSP00000521061.1

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

GnomAD2 exomes AF: 0.467 AC: 101139 AN: 216660 AF XY: 0.474

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 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

African (AFR) AF: 0.111 AC: 3670 AN: 32996

American (AMR) AF: 0.505 AC: 20690 AN: 40968

Ashkenazi Jewish (ASJ) AF: 0.480 AC: 12200 AN: 25408

East Asian (EAS) AF: 0.457 AC: 17964 AN: 39292

South Asian (SAS) AF: 0.495 AC: 41016 AN: 82814

European-Finnish (FIN) AF: 0.378 AC: 19600 AN: 51826

Middle Eastern (MID) AF: 0.444 AC: 2318 AN: 5218

European-Non Finnish (NFE) AF: 0.528 AC: 582197 AN: 1101910

Other (OTH) AF: 0.483 AC: 28631 AN: 59332

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

African (AFR) AF: 0.129 AC: 5356 AN: 41480

American (AMR) AF: 0.480 AC: 7334 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.486 AC: 1682 AN: 3464

East Asian (EAS) AF: 0.440 AC: 2271 AN: 5158

South Asian (SAS) AF: 0.508 AC: 2453 AN: 4828

European-Finnish (FIN) AF: 0.367 AC: 3879 AN: 10566

Middle Eastern (MID) AF: 0.414 AC: 121 AN: 292

European-Non Finnish (NFE) AF: 0.514 AC: 34907 AN: 67912

Other (OTH) AF: 0.408 AC: 863 AN: 2114

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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	3.4
DANN	Benign	0.56
PhyloP100		0.077
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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