chr8-21693288-A-T

Variant names:

• chr8-21693288-A-T
• rs1128397
• NM_001495.5:c.1385T>A

Variant summary

Our verdict is Benign. The variant received -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.

• 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
• Publications: 26 publications found

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

Our verdict: Benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001495.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GFRA2	NM_001495.5	MANE Select	c.1385T>A	p.Leu462Gln	missense	Exon 9 of 9	NP_001486.4
	GFRA2	NM_001165038.2		c.1070T>A	p.Leu357Gln	missense	Exon 8 of 8	NP_001158510.1
	GFRA2	NM_001165039.2		c.986T>A	p.Leu329Gln	missense	Exon 7 of 7	NP_001158511.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GFRA2	ENST00000524240.6	TSL:1 MANE Select	c.1385T>A	p.Leu462Gln	missense	Exon 9 of 9	ENSP00000428518.1
	GFRA2	ENST00000517892.5	TSL:1	c.1070T>A	p.Leu357Gln	missense	Exon 8 of 8	ENSP00000429979.1
	GFRA2	ENST00000518077.5	TSL:1	c.986T>A	p.Leu329Gln	missense	Exon 7 of 7	ENSP00000429206.1

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

GnomAD2 exomes AF: 0.382 AC: 93634 AN: 245262 AF XY: 0.387

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 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

African (AFR) AF: 0.335 AC: 11180 AN: 33376

American (AMR) AF: 0.295 AC: 13077 AN: 44326

Ashkenazi Jewish (ASJ) AF: 0.437 AC: 11383 AN: 26056

East Asian (EAS) AF: 0.444 AC: 17542 AN: 39538

South Asian (SAS) AF: 0.387 AC: 33250 AN: 85838

European-Finnish (FIN) AF: 0.345 AC: 18391 AN: 53308

Middle Eastern (MID) AF: 0.426 AC: 2454 AN: 5754

European-Non Finnish (NFE) AF: 0.405 AC: 449706 AN: 1110000

Other (OTH) AF: 0.405 AC: 24391 AN: 60258

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

African (AFR) AF: 0.343 AC: 14201 AN: 41404

American (AMR) AF: 0.323 AC: 4933 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.424 AC: 1473 AN: 3472

East Asian (EAS) AF: 0.440 AC: 2258 AN: 5136

South Asian (SAS) AF: 0.371 AC: 1783 AN: 4806

European-Finnish (FIN) AF: 0.327 AC: 3458 AN: 10564

Middle Eastern (MID) AF: 0.449 AC: 131 AN: 292

European-Non Finnish (NFE) AF: 0.411 AC: 27908 AN: 67934

Other (OTH) AF: 0.385 AC: 810 AN: 2106

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 v4.9

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
Eigen	Uncertain	0.22
Eigen_PC	Benign	0.14
FATHMM_MKL	Benign	0.75	D
LIST_S2	Benign	0.81	T
MetaRNN	Benign	0.0032	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	2.0	M
PhyloP100		2.3
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.067
Sift	Uncertain	0.029	D
Sift4G	Uncertain	0.0060	D
Polyphen		1.0	D
Vest4		0.31
MPC		0.17
ClinPred		0.021	T
GERP RS		2.9
Varity_R		0.23
gMVP		0.79
Mutation Taster		=95/5	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1128397; hg19: chr8-21550800; COSMIC: COSV60777641;