chr8-21693288-A-T

Position:

• chr8-21693288-A-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001495.5(GFRA2):​c.1385T>A​(p.Leu462Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.397 in 1,610,344 control chromosomes in the GnomAD database, including 128,185 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. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.38 (11078 hom., cov: 31)
  • Exomes 𝑓: 0.40 (117107 hom.)
• Consequence: GFRA2 NM_001495.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.34

Genes affected

GFRA2 (HGNC:4244): (GDNF family receptor alpha 2) Glial cell line-derived neurotrophic factor (GDNF) and neurturin (NTN) are two structurally related, potent neurotrophic factors that play key roles in the control of neuron survival and differentiation. The protein encoded by this gene is a member of the GDNF receptor family. It is a glycosylphosphatidylinositol(GPI)-linked cell surface receptor for both GDNF and NTN, and mediates activation of the RET tyrosine kinase receptor. This encoded protein acts preferentially as a receptor for NTN compared to its other family member, GDNF family receptor alpha 1. This gene is a candidate gene for RET-associated diseases. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Sep 2009]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0031813085).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.425 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GFRA2	NM_001495.5	c.1385T>A	p.Leu462Gln	missense_variant	9/9	ENST00000524240.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GFRA2	ENST00000524240.6	c.1385T>A	p.Leu462Gln	missense_variant	9/9	1	NM_001495.5	P1

Frequencies

GnomAD3 genomes AF: 0.378 AC: 57331 AN: 151770 Hom.: 11063 Cov.: 31

Gnomad AFR AF: 0.343

Gnomad AMI AF: 0.440

Gnomad AMR AF: 0.324

Gnomad ASJ AF: 0.424

Gnomad EAS AF: 0.440

Gnomad SAS AF: 0.370

Gnomad FIN AF: 0.327

Gnomad MID AF: 0.449

Gnomad NFE AF: 0.411

Gnomad OTH AF: 0.387

GnomAD3 exomes AF: 0.382 AC: 93634 AN: 245262 Hom.: 18377 AF XY: 0.387 AC XY: 51609 AN XY: 133242

Gnomad AFR exome AF: 0.336

Gnomad AMR exome AF: 0.289

Gnomad ASJ exome AF: 0.444

Gnomad EAS exome AF: 0.446

Gnomad SAS exome AF: 0.389

Gnomad FIN exome AF: 0.337

Gnomad NFE exome AF: 0.406

Gnomad OTH exome AF: 0.401

GnomAD4 exome AF: 0.399 AC: 581374 AN: 1458454 Hom.: 117107 Cov.: 35 AF XY: 0.400 AC XY: 289891 AN XY: 725246

Gnomad4 AFR exome AF: 0.335

Gnomad4 AMR exome AF: 0.295

Gnomad4 ASJ exome AF: 0.437

Gnomad4 EAS exome AF: 0.444

Gnomad4 SAS exome AF: 0.387

Gnomad4 FIN exome AF: 0.345

Gnomad4 NFE exome AF: 0.405

Gnomad4 OTH exome AF: 0.405

GnomAD4 genome AF: 0.378 AC: 57355 AN: 151890 Hom.: 11078 Cov.: 31 AF XY: 0.373 AC XY: 27662 AN XY: 74222

Gnomad4 AFR AF: 0.343

Gnomad4 AMR AF: 0.323

Gnomad4 ASJ AF: 0.424

Gnomad4 EAS AF: 0.440

Gnomad4 SAS AF: 0.371

Gnomad4 FIN AF: 0.327

Gnomad4 NFE AF: 0.411

Gnomad4 OTH AF: 0.385

Alfa AF: 0.407 Hom.: 9870

Bravo AF: 0.373

TwinsUK AF: 0.410 AC: 1521

ALSPAC AF: 0.390 AC: 1504

ESP6500AA AF: 0.333 AC: 1321

ESP6500EA AF: 0.399 AC: 3335

ExAC AF: 0.386 AC: 46651

Asia WGS AF: 0.369 AC: 1283 AN: 3478

EpiCase AF: 0.409

EpiControl AF: 0.405

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.46
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.13	T;T;.;.
Eigen	Uncertain	0.22
Eigen_PC	Benign	0.14
FATHMM_MKL	Benign	0.75	D
LIST_S2	Benign	0.81	.;T;T;T
MetaRNN	Benign	0.0032	T;T;T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	2.0	M;M;.;.
MutationTaster	Benign	0.083	P;P;P;P
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-1.6	N;N;N;N
REVEL	Benign	0.067
Sift	Uncertain	0.029	D;D;D;D
Sift4G	Uncertain	0.0060	D;D;D;D
Polyphen		1.0	D;D;D;.
Vest4		0.31
MPC		0.17
ClinPred		0.021	T
GERP RS		2.9
Varity_R		0.23
gMVP		0.79

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1128397; hg19: chr8-21550800; COSMIC: COSV60777641;